@article {pmid42964735,
year = {2026},
author = {Ghiasvand, K and Meftahi, GH},
title = {Black Myrobalan (Terminalia chebula) as a potential multitarget neuroprotective agent: Translational insights and future directions in neurodegenerative diseases.},
journal = {Biochemistry and biophysics reports},
volume = {48},
number = {},
pages = {102850},
pmid = {42964735},
issn = {2405-5808},
abstract = {Myrobalan or Haritaki (Terminalia chebula Retz.) has been integrated into Ayurvedic, Unani, and even Tibetan medicine systems for over 2000 years. The "King of Medicines" has traditionally been used for diverse ailments such as digestive issues, wound healing, and general body strengthening. Now, modern medicine is focusing on the myrobalan's potential neuroprotective properties and its use in Alzheimer's, Parkinson's, Huntington's, and amyotrophic lateral sclerosis (ALS) neurodegenerative disorders. These ailments are characterized by some combination of enduring oxidative damage, mitochondrial dysfunction, neuroinflammation, irregular protein aggregation, and progressive neuron cell death. Most of the current treatment options revolve around addressing the symptoms of the diseases, which is insufficient as the underlying disease continues to progress. There is an urgent need to devise therapies that work simultaneously on multiple disease pathways. Some of the noted secondary metabolites in T. chebula include hydrolyzable tannins like chebulinic and chebulagic acid as well as corilagin. Others occur as phenolic acids such as gallic and ellagic acid and flavonoids quercetin and kaempferol. Moreover, glycosides, sterols, and a wide range of alkaloids are also present. A number of these compounds are known to possess multifunctional biological properties like scavenging ROS, activating Nrf2/ARE signaling, downregulating pro-inflammatory mediators through blockade of NF-κB, and exerting protective effects on the mitochondria, as well as modulating apoptosis via Bcl-2 and caspases. T. chebula extracts and some isolated compounds have also been shown to improve cognitive function, reduce neuroinflammation, and protect dopaminergic neurons, and ameliorate neurotoxic effects of amyloid-β or α-synuclein through in vitro and in vivo animal studies. A review of the contributions from the phytochemistry, mechanism of action, preclinical, translational, and adjunctive applications of Terminalia chebula in neurodegenerative disease therapy is presented here.},
}

@article {pmid42959522,
year = {2026},
author = {Matta, C and Cheon, YH and Vágó, J and Mészár, Z and Kim, EH and Jiang, S and Balogh, A and Zana, M and Dinnyés, A and Jin, EJ},
title = {Engineered peroxisomes and patient-derived iPSC models as potential biomaterial platforms for precision neuroprotection in oxidative stress-driven central nervous system disorders.},
journal = {Materials today. Bio},
volume = {41},
number = {},
pages = {103752},
pmid = {42959522},
issn = {2590-0064},
abstract = {Peroxisomes couple hydrogen peroxide metabolism to lipid homeostasis, making their functions relevant to neurological disease and to the design of intracellular catalytic biomaterials. However, the strength of disease-specific evidence and the functions reproduced by current materials vary substantially. This narrative review distinguishes modified biological peroxisomes from artificial and biomimetic platforms and evaluates how patient-derived induced pluripotent stem cell (iPSC) models could support their development. We examine membrane chemistry, substrate permeability, enzyme retention, catalytic activity, cell targeting, blood-brain barrier transport, three-dimensional tissue penetration, and intracellular fate. We separate the established causal role of peroxisomal defects in primary peroxisomal disorders from associative or unresolved findings in Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Kleefstra syndrome is discussed as a hypothesis-generating neurodevelopmental model, without assuming a primary peroxisomal defect. Published artificial-organelle studies establish selected catalytic and delivery capabilities, but do not validate the integrated patient-specific CNS therapeutic strategy proposed here. We therefore outline a staged evaluation framework that combines materials characterization with mechanistic controls, differentiated neural cultures, multicellular models, animal pharmacology, safety, and manufacturing assessment. Comparison with conventional antioxidant carriers, plasmalogen supplementation, and PPAR agonists should determine whether compartmentalized catalysis offers a measurable advantage. We provide a platform classification, a disease-resolved evidence hierarchy, and a set of controls and measurable endpoints intended to make peroxisome-inspired constructs comparable across studies. Clinical development will require evidence of disease-relevant benefit beyond ROS reduction and an acceptable therapeutic window.},
}

@article {pmid42953823,
year = {2026},
author = {Chen, HW},
title = {Bypassing the Blood-Central Nervous System (CNS) Barrier: A Dual-Axis Framework for Amyotrophic Lateral Sclerosis (ALS) Utilizing Glymphatic-Lymphatic Clearance and In Situ Chaperone Synthesis.},
journal = {Cureus},
volume = {18},
number = {9},
pages = {e117043},
pmid = {42953823},
issn = {2168-8184},
abstract = {Amyotrophic lateral sclerosis (ALS) is characterized by prion-like propagation of misfolded TAR DNA-binding protein 43 (TDP-43) and superoxide dismutase 1 (SOD1) across motor neuron pools. Because any circulating pharmacological agent must cross the blood-brain and blood-spinal cord barriers (BBB and BSCB), this review proposes active craniospinal tensioning (ACT) as a mechanical, non-pharmacological route to disease modification that acts on cerebrospinal fluid (CSF) and venous pressure dynamics rather than requiring penetration of these barriers. ACT is proposed to engage a single Monro-Kellie/Queckenstedt pressure continuity through two concurrent mechanisms: suboccipital venous occlusion-rebound, hypothesized to transiently raise and release craniospinal CSF pressure via venous compression and thereby accelerate venous-side glymphatic efflux; and dural pull-recoil, hypothesized to generate a reciprocal CSF pressure gradient via spinal elongation, agitating perivascular CSF directly while inducing a coupled venous pressure gradient. Because both mechanisms act concurrently on a shared venous-side target, the combined maneuver is proposed to be more potent than either delivered alone, as in prior work on pelvis-stabilized axial spinal traction (PSAST), which lacks the occlusion-rebound component. A secondary, hypothesis-generating micro-biochemical axis, cerebral venous preconditioning (CVPC), proposes that the same occlusion-rebound cycle produces capillary/venule wall strain sufficient to activate heat shock factor 1 (HSF-1) across the neurovascular unit, independent of oxygen tension, with a possible but uncharacterized contribution from hypoxia-inducible factor 1-alpha (HIF-1α). The two routes are non-exclusive, with the macro-fluidic axis alone proposed as sufficient. This framework is entirely theoretical, requires preclinical and clinical validation, and is intended as a template for related proteinopathy-driven neurodegenerative diseases, including Parkinson's disease, Huntington's disease, spinocerebellar ataxia, and fatal familial insomnia, addressed in forthcoming work.},
}

@article {pmid42955216,
year = {2026},
author = {Oria, RS and Esomonu, UG and Sunday, KI and Oge, PA},
title = {Microglial perturbation in heavy metal-induced neuroinflammation and neurodegeneration: mechanisms, phenotypic plasticity, and therapeutic prospects.},
journal = {Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine},
volume = {},
number = {},
pages = {},
pmid = {42955216},
issn = {1572-8773},
abstract = {Heavy metal exposure has emerged as a significant environmental contributor to neurodegenerative disease, and a substantial body of mechanistic evidence implicates microglia in the pathological cascades that follow. Lead, cadmium, arsenic, manganese, copper, cobalt, mercury, and zinc disrupt central nervous system homeostasis through multiple cellular targets, but the resident innate immune cells of the brain are well placed to translate these insults into sustained neuroinflammation. Evidence for this critical narrative review was assembled through a purposive search of PubMed, MEDLINE, and Google Scholar for mechanistically informative studies reporting glial endpoints, with reference lists searched by hand and no systematic protocol applied. This review synthesizes current understanding of how individual metals engage microglial signaling networks, with particular attention to oxidative stress, NF-κB activation, NLRP3 inflammasome assembly, MAPK cascades, and suppression of the Nrf2 antioxidant axis. We examine the phenotypic spectrum that extends well beyond the classical M1/M2 dichotomy, including disease-associated microglia, lipid-droplet-accumulating microglia, and interferon-responsive states, and consider how metal-specific signatures map onto these transcriptional programs. Manganese-driven inflammasome assembly, cadmium-induced mitochondrial impairment, lead-mediated disruption of calcium homeostasis, and mercury-evoked autophagic dysfunction are discussed as illustrative examples of mechanistic divergence within a common neuroinflammatory framework. Glial responses to metal mixtures, which better represent real exposure than single-element designs, are considered separately, and the evidence for greater-than-additive effects is appraised. Downstream consequences for astrocyte reactivity, blood-brain barrier integrity, synaptic remodeling, and neuronal viability are placed in the context of Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Therapeutic avenues are appraised, including chelation, natural antioxidants, NLRP3 inhibitors, TREM2 modulation, and microglial replacement strategies. Methodological constraints, particularly the overreliance on BV-2 cells and acute high-dose exposure paradigms, are critically considered. The review concludes by identifying priorities for translational research, including longitudinal human cohort studies, single-cell transcriptomic profiling of metal-exposed microglia, and the development of region-specific exposure models that better reflect chronic environmental realities.},
}

@article {pmid41879495,
year = {2026},
author = {Singh, K and Sethi, P and Jain, D and Gupta, JK and Alsaidan, OA and Alzarea, SI and Kumar, A and Tabish, M and Sharma, MC},
title = {Emerging Roles of Small-molecule Derivatives in Modulating Neurodegenerative Pathways: From Molecular Targets to Therapeutic Applications.},
journal = {Mini reviews in medicinal chemistry},
volume = {26},
number = {20},
pages = {1625-1641},
pmid = {41879495},
issn = {1875-5607},
mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Small Molecule Libraries/chemistry/pharmacology/therapeutic use ; Animals ; Signal Transduction/drug effects ; *Neuroprotective Agents/chemistry/pharmacology ; },
abstract = {Neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease involve progressive neuronal dysfunction driven by mechanisms including protein aggregation, oxidative stress, mitochondrial impairment, and neuroinflammation. Current treatments are largely symptomatic, with limited disease-modifying options. Advances in medicinal chemistry have led to the development of small-molecule derivatives targeting specific pathological pathways, offering new therapeutic opportunities. This review summarizes recent progress in designing and optimizing such molecules to modulate amyloid-β metabolism, tau acetylation, α-synuclein aggregation, RNA-binding protein interactions, and NLRP3 inflammasome activation. Compounds acting on key signaling cascades, including PI3K/Akt, MAPK/ERK, Nrf2/ARE, and Wnt/β-catenin, are discussed, alongside drug repurposing strategies and preclinical-to-clinical translation. Special focus is given to microglial modulation, challenges in crossing the blood-brain barrier, and integration of precision medicine, metabolomics, and artificial intelligence into drug discovery. The review also highlights novel therapeutic concepts such as multi- target ligands, metal-chelation approaches, and modulation of neuroinflammatory pathways. Despite promising leads, significant challenges remain in optimizing pharmacokinetics, target selectivity, and delivery. Future directions include the identification of robust biomarkers, advanced imaging techniques, and computational tools to accelerate candidate validation. Collectively, smallmolecule therapeutics hold considerable promise in addressing unmet needs in neurodegenerative disease management, but their successful translation will require multidisciplinary approaches bridging molecular insights and clinical application.},
}

Humans
*Neurodegenerative Diseases/drug therapy/metabolism
*Small Molecule Libraries/chemistry/pharmacology/therapeutic use
Animals
Signal Transduction/drug effects
*Neuroprotective Agents/chemistry/pharmacology

@article {pmid42951629,
year = {2026},
author = {Inoue, H},
title = {[Disease modeling with iPSCs for pathophysiological elucidation and therapeutic research: establishment of an iPSC-based drug discovery platform centered on drug repositioning].},
journal = {[Rinsho ketsueki] The Japanese journal of clinical hematology},
volume = {67},
number = {9},
pages = {1145-1149},
doi = {10.11406/rinketsu.67.1145},
pmid = {42951629},
issn = {0485-1439},
mesh = {*Induced Pluripotent Stem Cells/cytology ; Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/pathology/genetics ; *Drug Repositioning ; *Drug Discovery/methods ; Animals ; *Models, Biological ; },
abstract = {Advances in induced pluripotent stem cell (iPSC) technology have enabled the establishment of patient-derived disease models, greatly accelerating research on disease mechanisms and drug discovery. Drug repositioning, which applies existing drugs to new indications, has emerged as an efficient therapeutic development strategy that reduces both development time and cost. This review summarizes recent progress in disease modeling and therapeutic research using iPSCs, focusing on amyotrophic lateral sclerosis (ALS). Motor neurons differentiated from ALS patient-derived iPSCs successfully recapitulated disease phenotypes and enabled compound screening. Using this platform, the Src/c-Abl inhibitor bosutinib was identified as a promising therapeutic candidate. Bosutinib promoted autophagy, reduced abnormal protein accumulation, and suppressed motor neuron degeneration in vitro and in vivo. Based on these findings, investigator-initiated clinical trials were conducted, demonstrating acceptable safety and suggesting potential efficacy in ALS patients. Furthermore, integration of iPSC-based analyses with biomarkers such as neurofilament light chain enabled patient stratification and suggested the feasibility of personalized therapeutic approaches. Future integration of iPSC models with artificial intelligence, genomic analysis, and real-world clinical data is expected to further enhance predictive precision and accelerate translational research. iPSC-based drug discovery therefore represents a promising platform for developing novel therapies for neurodegenerative diseases.},
}

*Induced Pluripotent Stem Cells/cytology
Humans
*Amyotrophic Lateral Sclerosis/drug therapy/pathology/genetics
*Drug Repositioning
*Drug Discovery/methods
Animals
*Models, Biological

@article {pmid42947522,
year = {2026},
author = {Sanghai, N and Vuong, B and Afridi, MSK and Leggett, S and Roghzai, H and Tranmer, GK},
title = {The Boron-Neuron Connection: The Potential of Boron-Containing Molecules for Treating Incurable Amyotrophic Lateral Sclerosis.},
journal = {ChemMedChem},
volume = {21},
number = {21},
pages = {},
pmid = {42947522},
issn = {1860-7187},
support = {202210PJT-495295//Canadian Institutes of Health Research (CIHR)/ ; RGPIN-2017-05938//Natural Sciences and Engineering Research Council of Canada (NSERC)/ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/pathology/metabolism ; Reactive Oxygen Species/metabolism ; Animals ; *Neuroprotective Agents/chemistry/pharmacology/therapeutic use ; *Boron Compounds/chemistry/pharmacology/therapeutic use ; *Neurons/drug effects/metabolism ; Blood-Brain Barrier/metabolism/drug effects ; *Boron/chemistry/pharmacology ; Molecular Structure ; Oxidative Stress/drug effects ; },
abstract = {BACKGROUND: Boron (B), a group 13 metalloid, has emerged as a versatile element at the intersection of chemistry, biology, and medicine. Its electron-deficient nature and ability to reversibly interconvert between trigonal planar (sp[2]) and tetrahedral (sp[3]) geometries enable dynamic covalent interactions with biological nucleophiles, making boron-containing compounds (BCCs) attractive pharmacophores that selectively interact with reactive oxygen species (ROS) and are ROS-responsive for therapeutic development. BCCs possess antioxidant, anti-inflammatory, and metal-chelating properties that make them attractive candidates for neurodegenerative diseases. Amyotrophic lateral sclerosis (ALS), a fatal and multifactorial motor neurodegenerative disorder, is characterized by oxidative stress, neuroinflammation, mitochondrial dysfunction, and metal dyshomeostasis, providing a strong rationale for exploring boron-based therapeutics.

METHODS: This review examines current literature on B chemistry, pharmacology, and translational applications, with emphasis on mechanisms relevant to ALS pathogenesis. This review focuses on ROS-responsive B scaffolds, blood-brain barrier (BBB) permeability, neuroprotective mechanisms, hormonal modulation, metal chelation, and emerging preclinical evidence supporting boron-based interventions.

CONCLUSIONS: BCCs represent a promising yet underexplored therapeutic platform for ALS and related neurodegenerative disorders. Their ROS-responsive, redox-modulating, and neuroprotective properties, combined with favorable CNS drug-like pharmacokinetics, offer a mechanistically distinct approach to disease modification. Emerging preclinical evidence strongly supports further translational investigation.},
}

Humans
*Amyotrophic Lateral Sclerosis/drug therapy/pathology/metabolism
Reactive Oxygen Species/metabolism
Animals
*Neuroprotective Agents/chemistry/pharmacology/therapeutic use
*Boron Compounds/chemistry/pharmacology/therapeutic use
*Neurons/drug effects/metabolism
Blood-Brain Barrier/metabolism/drug effects
*Boron/chemistry/pharmacology
Molecular Structure
Oxidative Stress/drug effects

@article {pmid42949499,
year = {2026},
author = {Poddar, K and Wahi, C},
title = {Deep learning models to detect neurodegenerative diseases across different modalities, datasets, and stages: A systematic review.},
journal = {Technology and health care : official journal of the European Society for Engineering and Medicine},
volume = {},
number = {},
pages = {9287329261502060},
doi = {10.1177/09287329261502060},
pmid = {42949499},
issn = {1878-7401},
abstract = {BackgroundNeurodegenerative diseases like Alzheimer's and Parkinson's pose significant diagnostic challenges because they are incurable. Their symptoms often overlap with those of normal ageing and involve progressive neuronal loss. This makes early prediction, proper diagnosis, and ongoing monitoring crucial at every stage of the disease. Deep learning has become a useful tool for handling different types of data. However, the performance of these models relies heavily on the availability and variety of data, making it important to characterize datasets.ObjectiveThis PRISMA-based systematic review looks at 111 studies from 2019 to April 2026, organized into three clinical stages of neurodegenerative diseases: early prediction, diagnosis, and progression.MethodsEach study is assessed across four dimensions: data type (neuroimaging or non-neuroimaging), datasets (open-access, self-created, or hybrid), deep learning model architecture, and the use of explainable AI.ResultsMRI is the only imaging modality that spans all three stages. Speech is the most common non-neuroimaging method for diagnosis, while gait is used only for diagnosis and progression. The ADNI and PPMI datasets are the most commonly used. Self-created datasets introduce new modalities such as ECG and iPSCs, which are not found in open-access datasets. CNNs are the leading models for neuroimaging tasks, while LSTMs and RNNs capture temporal patterns in longitudinal datasets. Survival models are exclusively used for ALS and LATE. Fewer than 6% of the studies used confirmed XAI. Only 2 of the 111 studies validated their results on an independent external cohort.ConclusionThis review is the only one that covers all three disease stages across multiple neurodegenerative diseases.},
}

@article {pmid42942116,
year = {2026},
author = {Ramadan, S and Panza, E and Orlacchio, A},
title = {Beyond Monogenic Inheritance: Emerging Genetic Architecture of Amyotrophic Lateral Sclerosis.},
journal = {International journal of molecular sciences},
volume = {27},
number = {20},
pages = {},
pmid = {42942116},
issn = {1422-0067},
support = {JALSDGC project to A.O.//Italian research Foundation for ALS/ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *Genetic Predisposition to Disease ; C9orf72 Protein/genetics ; RNA-Binding Protein FUS/genetics ; Superoxide Dismutase-1/genetics ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by marked genetic and phenotypic heterogeneity. Although pathogenic variants in major ALS genes, including C9ORF72, SOD1, TARDBP, and FUS, have provided fundamental insights into disease pathogenesis, many familial and most sporadic cases remain without a molecular diagnosis, suggesting a genetic architecture extending beyond coding variants and monogenic inheritance. Advances in genomic technologies have revealed contributions from deep-intronic and regulatory variants, structural rearrangements, repeat expansions, and other forms of genomic variation incompletely captured by standard diagnostic approaches. Evidence also indicates that combinations of rare variants with moderate or incomplete penetrance may contribute to disease susceptibility and clinical variability, supporting a multilayer model of ALS genetics. Population-specific variation and convergence of genetically diverse defects on common molecular pathways further complicate variant interpretation and disease classification. This review examines emerging components of ALS genetic architecture, including non-coding variation, structural variants, repeat expansions, oligogenic burden, ancestry-related gaps, and convergent neurodegenerative pathways. Integrating these genomic layers with functional and transcriptomic evidence may improve variant interpretation, diagnostic yield, patient stratification, and the development of mechanism-based precision therapies.},
}

Humans
*Amyotrophic Lateral Sclerosis/genetics
*Genetic Predisposition to Disease
C9orf72 Protein/genetics
RNA-Binding Protein FUS/genetics
Superoxide Dismutase-1/genetics

@article {pmid42946239,
year = {2026},
author = {Dale, A and Sattler, R},
title = {TDP-43 dysfunction destabilizes glial homeostatic identity in ALS/FTD.},
journal = {Brain research},
volume = {},
number = {},
pages = {150618},
doi = {10.1016/j.brainres.2026.150618},
pmid = {42946239},
issn = {1872-6240},
abstract = {TAR DNA-binding protein 43 (TDP-43) pathology is a defining feature of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Although TDP-43 dysfunction has traditionally been studied through a neuron-centric framework, increasing evidence demonstrates that astrocytes, microglia, and oligodendrocytes are also directly affected and actively contribute to disease progression. In this review, we examine how TDP-43 dysfunction disrupts lineage-specific glial homeostatic programs and promotes distinct pathological state transitions across major glial populations. In astrocytes, TDP-43 dysfunction impairs neurotransmitter regulation, metabolic and neuronal support, RNA homeostasis, and secretory signaling while promoting inflammatory and antiviral-like states. In microglia, altered TDP-43 disrupts inflammatory regulation, phagocytosis, lysosomal function, lipid metabolism, and stage-dependent protective responses. In oligodendrocytes, TDP-43 dysfunction compromises RNA processing, lineage maintenance, lipid metabolism, myelin integrity, and long-term axonal support. Together, these findings suggest that glial TDP-43 dysfunction cannot be reduced to a single generalized form of reactivity but instead reflects the breakdown of distinct cell type-specific identities required to maintain central nervous system homeostasis. A cross-glial framework integrating cell-autonomous dysfunction, non-cell-autonomous signaling, disease stage, and genetic context may therefore provide a more complete understanding of TDP-43 proteinopathy and its contribution to neurodegeneration across the ALS-FTD spectrum.},
}

@article {pmid42929812,
year = {2026},
author = {Zhang, N and Freeman, DD and Polster, BM},
title = {BAX, VDAC, Gasdermin, and Permeability Transition Pores in Inflammatory Mitochondrial DNA Release: Is This the "Hole" Story?.},
journal = {Cells},
volume = {15},
number = {20},
pages = {},
pmid = {42929812},
issn = {2073-4409},
support = {R01NS112212/NS/NINDS NIH HHS/United States ; R21NS133527/NS/NINDS NIH HHS/United States ; R21 NS133527 (B.M.P.)./NS/NINDS NIH HHS/United States ; },
mesh = {Humans ; *DNA, Mitochondrial/metabolism ; Animals ; *bcl-2-Associated X Protein/metabolism ; *Mitochondrial Permeability Transition Pore/metabolism ; *Voltage-Dependent Anion Channels/metabolism ; Mitochondria/metabolism ; *Inflammation/metabolism ; },
abstract = {Disease-modifying neuroprotective therapies for traumatic brain injury (TBI), stroke, and age-related neurodegenerative disorders have proven elusive. Interest in mitochondrial outer membrane permeabilization mechanisms as a drug target evolved from the 1990s discovery of BAX/BAK-mediated mitochondrial cytochrome c release as an apoptotic cell death trigger. However, enthusiasm waned as subsequent findings revealed that apoptosis is not the dominant cell death mechanism in the mature brain. The more recent discovery of mitochondrial DNA (mtDNA) as an inflammatory trigger produced renewed interest in mitochondrial permeability pathways. In particular, the DNA-sensing molecule cGAS and its downstream effector STING were implicated in the pathogenesis of several neurodegenerative conditions, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and TBI. Nevertheless, these findings raised a puzzling question: how does mtDNA, which resides in the mitochondrial matrix surrounded by double membranes, escape to initiate inflammatory responses without triggering cytochrome c-dependent cell death? Here, we review the many proposed mechanisms for mtDNA release, including several that do not require mitochondrial membrane holes, and discuss advances toward pharmacological targeting of these pathways. Identification of the specific mtDNA efflux pathway(s) proximal to maladaptive neuroinflammatory responses may yield new treatment strategies for AD, TBI, and other neurological diseases.},
}

Humans
*DNA, Mitochondrial/metabolism
Animals
*bcl-2-Associated X Protein/metabolism
*Mitochondrial Permeability Transition Pore/metabolism
*Voltage-Dependent Anion Channels/metabolism
Mitochondria/metabolism
*Inflammation/metabolism

@article {pmid42933736,
year = {2026},
author = {Chakraborty, W and Anand, A and Kumar, S and Roy, KK},
title = {Circadian aging and neurodegeneration: the emerging role of the melatonin-cortisol axis in brain homeostasis, disease progression, and precision chronomedicine.},
journal = {Frontiers in neuroendocrinology},
volume = {83},
number = {},
pages = {101292},
doi = {10.1016/j.yfrne.2026.101292},
pmid = {42933736},
issn = {1095-6808},
abstract = {Circadian aging may promote neurodegenerative illnesses by dysregulating the melatonin-cortisol axis. Low nighttime melatonin synthesis, blunted cortisol circadian cycles, abnormal clock-gene oscillation patterns, and sleep-wake architecture undermine central and peripheral circadian equilibrium with age. Neuroendocrine alterations produce oxidative stress, mitochondrial failure, pervasive neuroinflammation (CNS immune function loss), and proteostasis. Increasing Alzheimer's, Parkinson's, ALS, Huntington's, frontotemporal dementia, Lewy body disease, PTSD, and vascular cognitive impairment due to impaired glymphatic axonal clearance/blood-brain barrier dysregulation/synaptic degeneration/pathoproteopathic protein We examine how clock genes, melatonin signaling, hypothalamic-pituitary-adrenal axis administration, microglia reactivity, and immune-mediated metabolic dysregulation affect dementia. New endocrine, transcriptomic, multi-omics, and wearable-derived digital biomarkers, chronopharmacology (including melatonin receptor agonists), bright-light therapy, time-restricted eating with exercise chronotherapy guidance/synchronization, sleep optimization, and gut microbiota modulation This study addressed inter-individual circadian variability, genetic susceptibility to therapy timing, biomarker standardization, and clinical trial design. The melatonin-cortisol axis may identify and treat age-related neurodegenerative diseases with tailored treatment.},
}

@article {pmid42934257,
year = {2026},
author = {Okoshi, K and Aoki, Y},
title = {Neuromuscular junction pathology in amyotrophic lateral sclerosis and emerging molecular therapeutic strategies.},
journal = {Journal of human genetics},
volume = {},
number = {},
pages = {},
pmid = {42934257},
issn = {1435-232X},
abstract = {Traditionally conceptualized as a soma-centric pathology, amyotrophic lateral sclerosis (ALS) is a fatal, heterogeneous neurodegenerative disease. The suboptimal outcomes of central nervous system (CNS)-directed therapeutic strategies have necessitated a shift in focus toward the dying-back hypothesis. This hypothesis contends that synaptic disconnection and axonal retraction at the distal neuromuscular junction (NMJ) are early pathological events that may antedate overt motor neuron loss. This review systematically examines the NMJ as an early vulnerable and therapeutically tractable peripheral niche in ALS pathogenesis, rather than merely a downstream consequence of proximal proteinopathy. Evidence from human clinical samples and ALS mouse models, particularly SOD1-G93A mice, collectively supports the early vulnerability of the NMJ, with the temporal precedence of denervation, synaptic retraction, and mitochondrial dysfunction most clearly demonstrated in experimental models. We highlight how the breakdown of the tripartite synapse-comprising the motor terminal, skeletal muscle, and terminal Schwann cells (tSCs)-may disrupt essential neurotrophic signaling and local metabolic homeostasis. Furthermore, we discuss how advancements in humanized in vitro NMJ models and spatial transcriptomics provide unprecedented resolution into localized RNA dysmetabolism and bioenergetic failure. Finally, we evaluate emerging therapeutic strategies specifically designed to stabilize or restore the NMJ, including MuSK agonists and other NMJ-directed approaches. By recontextualizing the NMJ as a critical early site of vulnerability, we propose that targeting the peripheral synaptic microenvironment may offer a promising strategy for modifying the progression of ALS.},
}

@article {pmid42934377,
year = {2026},
author = {Wu, Y and Zhang, X and Gao, C and Zhang, Z and Liao, X and Kang, Y},
title = {The cGAS-STING Pathway in Neuroinflammation and Neurological Disease: Mechanisms, Disease Contexts, and Periphery-to-Brain Communication.},
journal = {Cellular and molecular neurobiology},
volume = {46},
number = {1},
pages = {},
pmid = {42934377},
issn = {1573-6830},
support = {2024MZFS007//Research Grant of Key Laboratory of Anesthesiology and Resuscitation, Ministry of Education/ ; 82272199//National Natural Science Foundation of China/ ; 2022YFC2504500//Key Technologies Research and Development Program/ ; },
mesh = {Humans ; Animals ; cGAS-STING Signaling Pathway ; *Nucleotidyltransferases/metabolism ; *Nervous System Diseases/metabolism/pathology ; *Brain/metabolism/pathology ; *Neuroinflammatory Diseases/metabolism/pathology ; *Membrane Proteins/metabolism ; Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase ; STING Protein ; Signal Transduction ; Inflammation/metabolism/pathology ; },
abstract = {Neurodegenerative disorders involve a strong inflammatory component, yet the underlying inflammatory mechanisms may be heterogeneous across disease stage, cell type, and systemic context. A key unresolved question is how cellular and systemic stress is converted into sustained neuroinflammation. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is an innate DNA-sensing hub that translates mislocalized self-DNA - derived from mitochondrial stress and mtDNA leakage, nuclear envelope instability, micronuclei formation, or impaired nucleic-acid disposal - into type I interferon, NF-kB, autophagy-related, and senescence-associated inflammatory programs. Rather than treating cGAS-STING as a universal disease-defining pathway, this review frames it as a context-dependent amplifier that becomes pathogenic when DNA-DAMP burden, defective mitochondrial quality control, neurovascular "leakage", and glial priming converge. We synthesize cell-type-specific evidence in microglia, astrocytes, neurons, and the neurovascular unit; compare mechanistic involvement across Alzheimer's disease, Parkinson's disease dementia and Lewy body disease, amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD), vascular and acute brain injury, and systemic inflammatory encephalopathies; and organize periphery-to-brain communication axes using an explicit evidence-grading framework. A distinctive contribution of this review is a two-hit model in which systemic inflammatory stressors and barrier dysfunction first lower cognitive resilience, followed by brain-resident mitochondrial/DNA damage programs that lock in complement-linked synaptopathy. We also evaluate pharmacological and lifestyle-based modulation, emphasizing biomarker-enriched trial design, CNS exposure, compartment-specific target engagement, and immune-safety constraints. This framework aims to clarify when, where, and in whom cGAS-STING modulation may preserve synapses and cognition without unacceptable immune trade-offs.},
}

Humans
Animals
cGAS-STING Signaling Pathway
*Nucleotidyltransferases/metabolism
*Nervous System Diseases/metabolism/pathology
*Brain/metabolism/pathology
*Neuroinflammatory Diseases/metabolism/pathology
*Membrane Proteins/metabolism
Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase
STING Protein
Signal Transduction
Inflammation/metabolism/pathology

@article {pmid42939346,
year = {2026},
author = {Alfaro-Rodríguez, A and Cortes-Altamirano, JL and Reyes-Long, S and Bonilla-Jaime, H and Avila-Camacho, FJ and Moreno-Villalba, LM and Herrera-López, ME and González-Maciel, A and Pérez-Guille, B and Soriano-Rosales, RE and Calderon-Guzman, D and Juaréz-Olguín, H},
title = {Glial Contributions to Pain in Neurodegenerative Disease Models: A Systematic Review of Microglial and Astrocytic Evidence.},
journal = {Brain sciences},
volume = {16},
number = {10},
pages = {},
pmid = {42939346},
issn = {2076-3425},
abstract = {Background/Objectives: Pain is a common and disabling non-motor manifestation of neurodegenerative disorders, but the contribution of glial cells to nociceptive processing remains incompletely understood. This systematic review evaluated evidence from preclinical models of neurodegenerative diseases linking microglial and astrocytic activity to pain. Methods: The protocol was prospectively registered in PROSPERO (CRD420251084310), and reporting followed PRISMA 2020. We conducted the original electronic search in PubMed/MEDLINE; during major revision, we conducted supplementary searches in Scopus and Web of Science Core Collection. Across the three sources, we identified 2248 records. After hierarchical deduplication by DOI, PMID, and normalized title, 1567 unique records were screened. Eligible in vivo studies assessed microglial and/or astrocytic alterations together with pain- or nociception-related outcomes. Risk of bias was independently evaluated by two investigators using the SYRCLE tool, and findings were synthesized qualitatively. Results: Twenty-six studies met the eligibility criteria: sixteen examined multiple sclerosis/experimental autoimmune encephalomyelitis (61.5%), seven Parkinson's disease (26.9%), two Alzheimer's disease-related models (7.7%), and one Huntington's disease model (3.8%); no eligible amyotrophic lateral sclerosis study was identified. Pain-related alterations involved inflammatory, neuroimmune, synaptic, and astrocyte-associated pathways, but the evidence was strongly model-dependent. Findings based on individual studies, including early astrocytic contributions in experimental autoimmune encephalomyelitis and altered inflammatory allodynia in an Alzheimer's disease model, are interpreted as study-specific observations requiring replication. Conclusions: The available evidence supports context-dependent associations between glial responses and nociceptive processing; however, marker specificity, EAE predominance, sex and age imbalance, and incomplete reporting of bias control procedures limit causal and cross-disease generalization.},
}

@article {pmid42939724,
year = {2026},
author = {Hutchison, LL and Parkes, MM and Pioro, EP},
title = {Serotonergic Dysfunction and the Interacting Role of TAR DNA-Binding Protein 43 in the Progression of Amyotrophic Lateral Sclerosis: A Scoping Review.},
journal = {Biomolecules},
volume = {16},
number = {10},
pages = {},
pmid = {42939724},
issn = {2218-273X},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/physiopathology ; *DNA-Binding Proteins/metabolism ; *Serotonin/metabolism ; Animals ; Disease Progression ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the loss of motor neurons and widespread neural dysfunction. Loss of serotonin (5-HT) signaling and TAR DNA-binding protein 43 (TDP-43) dysfunction have both been identified as contributing factors to disease progression, although their relationship has yet to be fully defined. The objective of this review was to assess whether any mechanistic links exist between serotonergic dysfunction and TDP-43 proteinopathy in ALS. A scoping review was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) guidelines. Databases were queried for the peer-reviewed literature concerning ALS pathophysiology, 5-HT, and TDP-43 (1946 to January 2026). Articles were screened and data independently extracted by two reviewers, which were subsequently synthesized qualitatively (n = 14). The current literature suggests that serotonergic dysfunction can be identified early in ALS pathology, indicated by decreased 5-HT concentration, degeneration of raphe projections, and changes in receptor activity. TDP-43 proteinopathy is a defining characteristic of ALS progression, characterized by cytoplasmic mislocalization and aggregation of TDP-43. Additionally, studies have identified bidirectional links between these dysfunctions: TDP-43 impairs serotonergic transmission, and 5-HT deficiency may drive pathological TDP-43 aggregation. Many mechanisms affected by both serotonergic and TDP-43 dysfunction are associated with disease progression including excitotoxicity, metabolic disturbances, and network hyperexcitability. Despite this, there is a lack of direct experimental evidence elucidating connections between these pathologies. Serotonergic dysfunction and TDP-43 proteinopathy may be linked by shared mechanisms in ALS, though specific causality has not been identified. Further research should aim to clarify the connection between these processes and discover therapeutic targets.},
}

Humans
*Amyotrophic Lateral Sclerosis/metabolism/pathology/physiopathology
*DNA-Binding Proteins/metabolism
*Serotonin/metabolism
Animals
Disease Progression

@article {pmid42939744,
year = {2026},
author = {Mohamed, YK and Yan, LJ},
title = {Edaravone for Potential Mitigation of Oxidative Stress and Inflammation in Kidney Disease.},
journal = {Biomolecules},
volume = {16},
number = {10},
pages = {},
pmid = {42939744},
issn = {2218-273X},
mesh = {Humans ; *Oxidative Stress/drug effects ; *Edaravone/therapeutic use/pharmacology ; Animals ; *Inflammation/drug therapy/metabolism ; *Kidney Diseases/drug therapy/metabolism/pathology ; Anti-Inflammatory Agents/therapeutic use/pharmacology ; Signal Transduction/drug effects ; Free Radical Scavengers/therapeutic use/pharmacology ; },
abstract = {Edaravone (EDA) is a synthetic free-radical scavenger FDA-approved for amyotrophic lateral sclerosis (ALS) treatment in the United States and is used clinically for treatment of acute ischemic stroke in Japan and other countries. While its antioxidant activity has been the primary focus of investigation in the mitigation of oxidative-stress-related injury, EDA exhibits anti-inflammatory, anti-fibrotic, anti-apoptotic, and anti-necrotic effects in animal models. These properties make it a potentially attractive therapeutic agent for kidney disease, where oxidative stress and inflammation contribute to renal cell injury, mitochondrial dysfunction, and progression of disease. In this review, we cover the underlying mechanisms of oxidative stress and inflammation in renal injury, and pharmacological and free-radical-scavenging mechanisms of EDA. Preclinical evidence in several kidney diseases, including ischemic/reperfusion injury, nephrotoxin-induced disease, and diabetic kidney disease, has been used to assess EDA for efficacy. In addition, we explore the modulatory roles of key signaling pathways, such as Nrf2 and NF-κB, in protective effects of EDA against oxidative stress, inflammation, mitochondrial dysfunction, apoptosis, necrosis, and fibrosis. Finally, we highlight the potential of EDA as a therapy in future clinical applications for various kidney diseases such as acute kidney injury (AKI) and chronic kidney disease (CKD). It should also be emphasized that as EDA's renal efficacy evidence described in this review is largely limited to animal studies, robust human clinical data are lacking. Therefore, additional clinical studies are still needed to fully elucidate the efficacy, safety, and benefits of EDA for prevention and treatment of human kidney disease.},
}

Humans
*Oxidative Stress/drug effects
*Edaravone/therapeutic use/pharmacology
Animals
*Inflammation/drug therapy/metabolism
*Kidney Diseases/drug therapy/metabolism/pathology
Anti-Inflammatory Agents/therapeutic use/pharmacology
Signal Transduction/drug effects
Free Radical Scavengers/therapeutic use/pharmacology

@article {pmid42940139,
year = {2026},
author = {Carata, E and Mariano, S and Tenuzzo, BA and Panzarini, E},
title = {Advancing the Translational Pipeline: From In Vivo and In Vitro 2D Models to Next-Generation Cell Culture Models for Amyotrophic Lateral Sclerosis Modelling and Drug Discovery.},
journal = {Biomedicines},
volume = {14},
number = {10},
pages = {},
pmid = {42940139},
issn = {2227-9059},
abstract = {Background: Amyotrophic lateral sclerosis (ALS) is still a global health challenge, as there is no effective treatment due to the inadequacy of conventional experimental platforms for comprehending pathogenic mechanisms and developing therapy. Objectives: This review details the recent progress and clinical utility of next-generation iPSC-derived 3D in vitro systems integrated with microfluidics, CRISPR-Cas9 gene editing, multi-omics readouts, and AI-based machine learning, which are emerging as transformative platforms for recapitulating key ALS pathological hallmarks. Methods: A literature search was performed using PubMed and Web of Science, including only English-language publications. All the published papers collected covered the period from January 2015 to June 2026. Results: Human induced pluripotent stem cell (iPSC) cerebral organoids, assembloids, and organ-on-a-chip technologies are revolutionizing research into ALS by providing a way to model the complex spatial organization, cellular heterogeneity, and neural network dynamics of the human brain. Moreover, recent bioengineering advancements enable the inclusion of functional neurovascular units, the integration of resident immune cells (microglia), and the use of 3D bioprinting to accelerate the functional maturation of age-related phenotypes. CRISPR-Cas9 genome editing, OMICS, and machine learning improve tools for studying ALS and identifying therapeutic targets. Conclusions: Novel cell culture models may bridge the gap between preclinical animal models and human clinical trials and reduce the duration and costs of translation. Future work is likely to integrate bioprinting with organ-on-chip microfluidics, CRISPR-based genetic editing, and multi-omics readouts to build increasingly faithful, patient-specific ALS models for both basic research and precision therapeutics.},
}

@article {pmid42941856,
year = {2026},
author = {Gómez-Pérez, CA and Ramírez-García, MÁ and Yescas-Gómez, P},
title = {The Role of SOD1 and Oxidative Stress in Amyotrophic Lateral Sclerosis: An Overview.},
journal = {International journal of molecular sciences},
volume = {27},
number = {20},
pages = {},
pmid = {42941856},
issn = {1422-0067},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/therapy/pathology ; *Superoxide Dismutase-1/genetics/metabolism ; *Oxidative Stress ; Animals ; Reactive Oxygen Species/metabolism ; Mutation ; Motor Neurons/metabolism/pathology ; Signal Transduction ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disorder that selectively affects motor neurons. The median survival time after diagnosis is 2 to 5 years. Oxidative stress (OS), driven mainly by reactive oxygen species (ROS), plays a central role in motor neuron (MN) degeneration. In this narrative review, we analyse the pathogenic role of SOD1 variants and their contribution to OS in ALS. SOD1 mutations alter the Cu/Zn superoxide dismutase enzyme, thereby promoting oxidative damage and triggering neuroinflammatory cascades via the MAPK, NF-κB and Nrf2/ARE signalling pathways. We also discuss emerging proteomic and machine-learning biomarkers, as well as the current therapeutic landscape. Riluzole and edaravone are approved treatments, while AMX0035 was approved in 2022 but withdrawn in 2024. Masitinib and EPI-589 remain investigational. In the realm of genetic therapies, the antisense oligonucleotide tofersen received accelerated FDA approval in 2023 for SOD1-ALS, primarily due to its ability to reduce plasma neurofilament light chain levels. However, the clinical benefit remains modest. RNA interference has reached human trials, while CRISPR/Cas9 remains in the preclinical stage. Both approaches have shown promising results in experimental models. Further research into ALS pathogenesis is needed to develop treatments that integrate antioxidant, anti-inflammatory, and gene-editing strategies.},
}

Humans
*Amyotrophic Lateral Sclerosis/metabolism/genetics/therapy/pathology
*Superoxide Dismutase-1/genetics/metabolism
*Oxidative Stress
Animals
Reactive Oxygen Species/metabolism
Mutation
Motor Neurons/metabolism/pathology
Signal Transduction

@article {pmid42942089,
year = {2026},
author = {Lv, X and Huang, M and Long, W and Li, X and Hu, Z and Feng, Y and Du, J and Long, Q and Chen, Y and Shi, M and Qin, D},
title = {Epigenetic Mechanisms in Neurodegenerative Diseases: From Genetic Regulation to Therapeutic Potential.},
journal = {International journal of molecular sciences},
volume = {27},
number = {20},
pages = {},
pmid = {42942089},
issn = {1422-0067},
support = {YPKLS2025-029//Yunnan Key Laboratory of Integrated Traditional Chinese and Western Medicine for Chronic Dis-ease in Prevention and Treatment/ ; KUST-KH2022017Y//Kunming University of Science and Technology & the First People's Hospital of Yunnan Province Joint Special Project on Medical Research/ ; 202401AY070001-135//Yunnan Provincial Department of Science and Technology-Kunming Medical University Joint Special Project/ ; },
mesh = {Humans ; *Epigenesis, Genetic ; *Neurodegenerative Diseases/genetics/therapy/metabolism ; Animals ; DNA Methylation ; Gene Expression Regulation ; RNA Methylation ; Biomarkers/metabolism ; Histones/metabolism ; Epitranscriptome ; },
abstract = {Neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), are multifactorial disorders in which genetic susceptibility alone cannot account for sporadic onset, clinical diversity, or age-dependent progression. Epigenetic mechanisms-DNA methylation, histone modifications, non-coding RNAs, and m6A RNA methylation-bridge environmental and intracellular cues to stable gene expression changes. Emerging evidence associates epigenetic dysregulation with amyloid-β/tau pathology in AD, α-synuclein pathology in PD, and TDP-43/C9orf72-associated toxicity in ALS, while functional studies suggest that selected epigenetic alterations may contribute to these processes. In this narrative review, we distinguish associative, functional, and mechanistic evidence using claim-specific criteria based on experimental perturbation, direct molecular assessment, and pathway-dependence or rescue testing, while considering the study system. We further evaluate the translational promise of epigenetic biomarkers in liquid biopsies, while emphasizing the major barriers that separate bench findings from bedside application, including poor target specificity, limited blood-brain barrier penetration, and the absence of biomarker-guided patient stratification. By integrating pathological mechanisms, biomarker development, and therapeutic strategies, this review argues that future epigenetic research in neurodegeneration must prioritize causal validation, CNS-penetrant drug development, and prospective trials integrating epigenetic profiling to achieve meaningful clinical impact.},
}

Humans
*Epigenesis, Genetic
*Neurodegenerative Diseases/genetics/therapy/metabolism
Animals
DNA Methylation
Gene Expression Regulation
RNA Methylation
Biomarkers/metabolism
Histones/metabolism
Epitranscriptome

@article {pmid42579090,
year = {2026},
author = {Filippi, L and Nuvoli, S and Spanu, A and Palumbo, B},
title = {Mapping the Synaptome in Neurodegeneration: Emerging Clinical Applications of SV2A PET Imaging.},
journal = {Molecular diagnosis & therapy},
volume = {30},
number = {6},
pages = {845-863},
pmid = {42579090},
issn = {1179-2000},
support = {Ricerca Corrente//Ministero della Salute/ ; },
mesh = {Humans ; *Positron-Emission Tomography/methods ; *Neurodegenerative Diseases/diagnostic imaging/metabolism/pathology ; *Nerve Tissue Proteins/metabolism ; *Membrane Glycoproteins/metabolism ; *Synapses/metabolism/pathology ; Animals ; Brain/diagnostic imaging/metabolism ; },
abstract = {Synaptic loss is a core pathological feature of neurodegenerative disorders and closely relates to cognitive and functional decline. Positron emission tomography (PET) targeting synaptic vesicle glycoprotein 2A (SV2A) has recently emerged as a promising tool for the indirect assessment of presynaptic alterations in the living human brain. This leading article discusses the evolving clinical landscape of SV2A PET across the neurodegenerative spectrum, emphasizing its translational trajectory and emerging applications. Current evidence spans Alzheimer's disease (AD), other dementias, movement disorders, Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). The literature is currently dominated by PET with [[11]C]UCB-J, while [[18]F]-labeled tracers, particularly [[18]F]SynVesT-1, are expanding clinical feasibility through longer half-life and broader distribution potential. Across disorders, PET consistently detected SV2A reductions that frequently correlated with cognition, disease severity, and complementary biomarkers, including amyloid, tau, glucose metabolism, and dopaminergic imaging. Although the field remains limited by small cohorts, heterogeneous quantification strategies, and incomplete longitudinal validation, SV2A PET is rapidly evolving into a promising translational tool for studying synaptopathies and monitoring disease progression.},
}

Humans
*Positron-Emission Tomography/methods
*Neurodegenerative Diseases/diagnostic imaging/metabolism/pathology
*Nerve Tissue Proteins/metabolism
*Membrane Glycoproteins/metabolism
*Synapses/metabolism/pathology
Animals
Brain/diagnostic imaging/metabolism

@article {pmid42925619,
year = {2026},
author = {Moreira, JVA and Pinheiro, CVA and de Souza, RF and Chiappa, GR and Ramos, SC and da Silva de Magalhães, MJ and de Aguiar, DR and Dos Santos, DF},
title = {The clinical spectrum of suicide-related outcomes in amyotrophic lateral sclerosis: A systematic review and meta-analysis.},
journal = {General hospital psychiatry},
volume = {103},
number = {},
pages = {204-212},
doi = {10.1016/j.genhosppsych.2026.10.002},
pmid = {42925619},
issn = {1873-7714},
abstract = {OBJECTIVE: To synthesize clinically distinct suicide-related outcomes in amyotrophic lateral sclerosis (ALS) and comparative suicide risk without pooling non-equivalent constructs.

METHODS: We searched MEDLINE, Embase, Scopus, PsycINFO, the Virtual Health Library, and SciELO through March 17, 2026, and updated all searches for March 18 through October 9, 2026. We included observational reports of predefined suicide-related outcomes. Outcomes with at least 3 independent studies were pooled using random-effects generalized linear mixed models for proportions and a Hartung-Knapp model for comparative estimates. We used Joanna Briggs Institute tools and adapted GRADE.

RESULTS: Twenty-eight reports representing 26 independent cohorts were included; 21 cohorts contributed quantitative data. Active suicidal ideation was 43% (23/53; 95% CI, 30%-58%) in an end-stage cohort and 14% (10/71; 95% CI, 7%-24%) in a general clinic cohort; these estimates were not pooled. Hypothetical consideration of assisted dying was 50% (95% CI, 41%-59%; I[2] = 49%; 95% prediction interval, 21%-79%; 4 studies). Crude suicide mortality rates were 0.16 and 0.36 per 100 person-years in 2 cohorts. Three registry or administrative cohorts yielded a relative suicide-risk estimate of 4.6 (95% CI, 2.5-8.5; 95% prediction interval, 0.4-53.6). Certainty was low or very low.

CONCLUSIONS: Suicide-related experiences in ALS are clinically distinct. Clinicians should clarify meaning, assess intent and immediacy, evaluate decision-making capacity and treatable psychiatric symptoms, and address palliative and psychosocial needs. A death wish or assisted-dying preference should not be assumed to indicate active suicidal intent.},
}

@article {pmid42927744,
year = {2026},
author = {Mishchenko, TA and Grechukhina, AA and Kulikov, SS and Olajide, OJ and Mitroshina, EV and Krysko, DV and Vedunova, MV},
title = {When the Brain Signals Danger: Roles of Calreticulin and HMGB1 in Cell Death Mechanisms in Neurooncology and Neurodegeneration.},
journal = {Biochemistry. Biokhimiia},
volume = {91},
number = {10},
pages = {1822-1841},
doi = {10.1134/S0006297926601565},
pmid = {42927744},
issn = {1608-3040},
mesh = {Humans ; *HMGB1 Protein/metabolism ; *Calreticulin/metabolism ; Animals ; *Neurodegenerative Diseases/metabolism/pathology ; *Brain/metabolism/pathology ; Cell Death ; Signal Transduction ; Alarmins/metabolism ; },
abstract = {Contrary to the classical paradigm of brain immune privilege, damage-associated molecular patterns (DAMPs) act as key mediators in the dialogue between CNS cells and the immune system, determining pathways of immune response development. This review examines the role of key DAMPs - calreticulin (CRT) and high-mobility group box 1 protein (HMGB1) - in the functioning of CNS under normal conditions and during the development of neuropathologies, particularly oncological and neurodegenerative processes. Under normal conditions, CRT and HMGB1 ensure functioning of the brain, acting as necessary effectors of neurogenesis and homeostatic plasticity. In neurooncology, exposure of CRT on the surface of dying cells and release of HMGB1 serve as powerful adjuvant signals for antigen-presenting cells, inducing immunogenic cell death (ICD). Particular attention is given to the mechanisms of passive HMGB1 release during various types of regulated cell death (apoptosis, necroptosis, pyroptosis, ferroptosis, cuproptosis), as well as to the role of redox modifications of the protein, which determine its pro-inflammatory, immunogenic, or tolerogenic properties. In neurodegeneration (Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis), excessive DAMP release exacerbates the development of chronic neuroinflammation, disrupts integrity of the blood-brain barrier (BBB), and forms a vicious cycle of pathological changes. Detection of CRT and HMGB1 in biological fluids or brain tissues has important prognostic potential, and regulation of their signaling pathways opens promising approaches for overcoming tumor resistance or inhibiting progressive neurodegenerative changes in the brain.},
}

Humans
*HMGB1 Protein/metabolism
*Calreticulin/metabolism
Animals
*Neurodegenerative Diseases/metabolism/pathology
*Brain/metabolism/pathology
Cell Death
Signal Transduction
Alarmins/metabolism

@article {pmid42925434,
year = {2026},
author = {Shah, A and Godad, A and Bagwe Parab, S},
title = {Unlocking therapeutic potential of Wnt signaling pathway in neurodegenerative diseases.},
journal = {Metabolic brain disease},
volume = {41},
number = {1},
pages = {},
pmid = {42925434},
issn = {1573-7365},
mesh = {Humans ; *Neurodegenerative Diseases/metabolism/drug therapy ; *Wnt Signaling Pathway/drug effects/physiology ; Animals ; Blood-Brain Barrier/metabolism/drug effects ; },
abstract = {The Wnt Signaling pathway is a regulatory network that is highly conserved in the central nervous system and is essential for the survival of neurons, synaptic plasticity, and the blood-brain barrier's integrity. The pathophysiology of major neurodegenerative and neurological disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and traumatic brain injury (TBI), is highly influenced by canonical and non-canonical Wnt Signaling dysregulation, according to increasingly compelling evidence. In addition to emphasising common molecular events such as GSK-3β overactivation, β-catenin destabilisation, neuroinflammation, synaptic dysfunction, and BBB disruption, this study offers a comparative and mechanistic overview of Wnt pathway changes across various illnesses. This article identifies overlapping treatment targets, such as GSK-3β, DKK1, LRP5/6, and Wnt ligands, by integrating common and disease-specific Wnt-associated pathways, in contrast to traditional disease-specific reviews. Furthermore, new translational approaches involving natural substances, Wnt modulators, and pathway-targeted treatments are critically examined. All things considered, this study presents Wnt Signaling as a potential neuroprotective and regenerative target for upcoming precision-based treatments in neurodegenerative disorders.},
}

Humans
*Neurodegenerative Diseases/metabolism/drug therapy
*Wnt Signaling Pathway/drug effects/physiology
Animals
Blood-Brain Barrier/metabolism/drug effects

@article {pmid42923269,
year = {2026},
author = {Shen, C and Wu, XT and Yin, H and Zuo, JL and Zhang, CH and Cao, F and Zhang, Y and Tian, ZY and Robinson, N and Liu, JP},
title = {Selected traditional Chinese medicines for treating amyotrophic lateral sclerosis: a Bayesian network meta-analysis based on randomised controlled trials.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1706211},
pmid = {42923269},
issn = {1663-9812},
abstract = {OBJECTIVE: To assess the effectiveness of specific Traditional Chinese Medicine (TCM) therapies for Amyotrophic Lateral Sclerosis (ALS) using Bayesian network meta-analysis.

METHODS: PubMed, the Cochrane Library, EMBASE, Web of Science, and four Chinese databases up to 15th December 2024 was searched, including RCTs on adult Amyotrophic Lateral Sclerosis patients treated with TCM therapies (Chinese herbal medicine, preparations, non-pharmacological treatments) alone or combined with conventional treatments. Controls included no intervention, placebo, conventional treatments, or combinations. Primary outcomes were functional status (ALSFRS, ALSFRS-R, AALSS, m-Norris scales). Bayesian network meta-analysis compared treatment effects and calculated SUCRA values.

RESULTS: Thirty-five RCTs involving 27 TCM therapies were included. No significant differences in functional status or quality of life were found among TCM therapies, ICT, Riluzole alone, and Riluzole plus placebo. For functional status, Shenmai injection + ICT (SUCRA 0.735 for ALSFRS, 0.870 for ALSFRS-R), Jiweiling injection + placebo (SUCRA 0.868 for ALSFRS), Jiawei Sijunzi decoction alone (SUCRA 0.739 for ALSFRS-R), Acupuncture + rehabilitation exercises + Riluzole (SUCRA 0.928 for AALSS, 0.863 for m-Norris) and Shenzhe Jiangqi powder + placebo (SUCRA 0.860 for m-Norris) had the highest probabilities of being superior treatment. For quality of life, Thunder fire moxibustion + Riluzole and Jiweiling injection + placebo for ALSAQ-40 were favorable.

CONCLUSION: Despite no significant differences in functional status among TCM therapies, ICT, Riluzole alone, and Riluzole plus placebo, Jiweiling injection, Shenmai injection, Jiawei Sijunzi decoction, and Shenzhe Jiangqi powder may be regarded as candidate preparations for ALS patients. Future research should focus on real-world data to explore long-term effects and practical benefits.

https://inplasy.com/inplasy-2024-8-0050/, identifier INPLASY202480050.},
}

@article {pmid42918426,
year = {2026},
author = {Kipanyula, MJ},
title = {Neurodegeneration in sub-Saharan Africa: Intersections of biological ageing, genomic diversity and the lifetime exposome.},
journal = {Ageing research reviews},
volume = {123},
number = {},
pages = {103429},
doi = {10.1016/j.arr.2026.103429},
pmid = {42918426},
issn = {1872-9649},
abstract = {Neurodegenerative diseases are emerging as an important consequence of population ageing in sub-Saharan Africa (SSA), but their scientific relevance extends beyond a projected rise in case numbers. SSA combines exceptional human genomic diversity with marked heterogeneity in vascular and metabolic risk, infection, nutrition, occupational exposures, air pollution, and access to health care. This combination creates an underused setting in which to study why biological ageing produces neurodegeneration in some individuals but relative resilience in others. This review critically synthesises evidence on Alzheimer's disease and related dementias, Parkinson's disease, amyotrophic lateral sclerosis/frontotemporal degeneration, Huntington's disease and related disorders, focusing on the intersection between hallmarks of ageing, disease-specific proteinopathies, ancestry and the lifetime exposome. Age-associated loss of proteostasis, mitochondrial dysfunction, impaired autophagy, chronic inflammation, neurovascular injury and genomic/epigenomic instability provide a mechanistic scaffold on which genetic susceptibility and cumulative exposures may act. Yet African evidence remains dominated by cross-sectional clinical phenotyping; neuropathology, longitudinal biomarkers, multi-omics and measured environmental exposures remain sparse. Recent African-ancestry Parkinson's disease genomics and emerging plasma biomarker studies demonstrate that ancestry-inclusive molecular neuroscience is feasible and can generate findings not predictable from European-ancestry datasets. The next phase should therefore move beyond documenting underdiagnosis toward longitudinal, biologically anchored cohorts that integrate phenotype, genomics, blood biomarkers, neuroimaging, exposomics, digital measures and health-system outcomes. This review proposes a research framework centred on biological ageing, gene-environment interaction and resilience. Such work would improve the validity of prevention, diagnosis and therapeutic translation in African populations while contributing globally to a more complete biology of neurodegenerative ageing.},
}

@article {pmid42918614,
year = {2026},
author = {Speranza, J and Gale-Rogers, C and Stretch, AC and West, RJH},
title = {Drosophila Models of Human Neurodegenerative Diseases.},
journal = {Current opinion in insect science},
volume = {},
number = {},
pages = {101639},
doi = {10.1016/j.cois.2026.101639},
pmid = {42918614},
issn = {2214-5753},
abstract = {In his book Insects and the Life of Man: Collected Essays on Pure Science and Applied Biology, Sir V. B. Wigglesworth examined how a fundamental understanding of insect physiology and biology can be applied to some of society's greatest challenges, including human health. Here we reflect on how, in the 50 years since his book's publication, Drosophila melanogaster have played a critical role in advancing our understanding of human neurodegenerative diseases. Focusing on Parkinson's disease, Huntington's disease, and the frontotemporal dementia / amyotrophic lateral sclerosis spectrum, we examine the role Drosophila have played in elucidating fundamental mechanisms of neurodegeneration, identifying therapeutic targets, and dissecting the complex interplay that exists between genetics and environmental factors. Together these studies highlight how Drosophila models continue to provide critical insight into the molecular mechanisms underpinning neurodegeneration and provide a fundamental pre-clinical model in which we can accelerate research into human neurodegenerative conditions.},
}

@article {pmid42919989,
year = {2026},
author = {Rossini, E and Garibaldi, M and Hanna, MG and Pitceathly, RDS and Pizzamiglio, C},
title = {Mitochondrial dysfunction in neurology: biomarkers and clinical implications.},
journal = {Nature reviews. Neurology},
volume = {},
number = {},
pages = {},
pmid = {42919989},
issn = {1759-4766},
abstract = {Mitochondrial dysfunction is increasingly recognized as a shared downstream pathogenic mechanism across a wide spectrum of neurological disorders, ranging from primary mitochondrial diseases to conditions including amyotrophic lateral sclerosis, Alzheimer disease, Parkinson disease, multiple sclerosis, hereditary ataxias and idiopathic inflammatory myopathies. This Review examines the role of mitochondrial biomarkers in improving diagnostic accuracy, patient stratification and monitoring of disease progression and therapeutic response. Primary mitochondrial diseases are presented as proof-of-concept models of impaired oxidative phosphorylation, providing a framework for biomarker identification and validation with translational relevance to other neurological diseases. Mitochondrial biomarkers can be broadly categorized into four domains: fluid biomarkers, reflecting metabolic alterations and stress signalling; genetic biomarkers, capturing mitochondrial DNA integrity and dynamics; multi-omics approaches, integrating transcriptomic, proteomic and metabolomic signatures; and imaging biomarkers, enabling in vivo assessment of structural and functional consequences of mitochondrial dysfunction. Across disorders, these biomarkers reveal shared disturbances in bioenergetics, redox homeostasis, mitochondrial genome maintenance and inflammatory signalling. However, clinical implementation remains limited by methodological heterogeneity, biological variability and reduced disease specificity. Integrated, multimodal biomarker strategies, combined with longitudinal validation, will be essential for supporting precision medicine and guiding the development of therapies to target mitochondrial pathways in neurology.},
}

@article {pmid42920457,
year = {2026},
author = {Malik, A and Ferdousi, M and Azmi, S and Malik, RA},
title = {Corneal Confocal Microscopy (CCM) in Patients With Central Neurodegenerative Disease.},
journal = {Cureus},
volume = {18},
number = {9},
pages = {e116756},
pmid = {42920457},
issn = {2168-8184},
abstract = {Corneal confocal microscopy (CCM) is a rapid, non-invasive ophthalmic imaging technique that enables detailed visualization and quantification of small corneal nerve fibres. Although initially developed for the assessment of diabetic neuropathy, its application has broadened substantially, with increasing evidence supporting its value in a range of central neurodegenerative diseases. This narrative review synthesizes current findings on the use of CCM in dementia, multiple sclerosis, stroke, burning mouth syndrome, amyotrophic lateral sclerosis, trigeminal neuralgia, migraine and Parkinson's disease. Across these conditions, CCM consistently identifies measurable alterations in corneal nerve fibre density, length, branching and morphology, as well as changes in corneal immune cell populations. These structural abnormalities frequently correlate with disease severity, functional decline and clinical progression. In some disorders, CCM demonstrates diagnostic performance comparable to or exceeding existing biomarkers, and offers distinct advantages as a non-invasive, repeatable and objective measure that can detect early or subclinical neurodegeneration. Corneal confocal microscopy also shows potential as a prognostic and monitoring tool, particularly in conditions with limited reliable biomarkers. It may help stratify risk, track therapeutic response, and provide surrogate endpoints for clinical trials. Despite these strengths, several limitations remain, including modest sample sizes in some studies, variability in image interpretation, and difficulties differentiating between neurodegenerative conditions with overlapping patterns of nerve loss. Emerging automated analysis methods and artificial intelligence-based algorithms may help address these challenges by improving accuracy, reproducibility, and scalability. Overall, CCM represents a promising technique that bridges ophthalmology and neurology. A growing body of literature supports its utility across multiple neurodegenerative diseases, and further large-scale, longitudinal studies may help establish its role within routine clinical assessment and research.},
}

@article {pmid42921272,
year = {2026},
author = {He, Z and Zeng, J and Wang, G and Li, Y and Zhang, F},
title = {Neurodegenerative Diseases: Epidemiology, Risk Factors, Classification, Pathophysiology, Clinical Features, Diagnosis, and Therapeutic Strategies.},
journal = {MedComm},
volume = {7},
number = {11},
pages = {e71090},
doi = {10.1002/mco2.71090},
pmid = {42921272},
issn = {2688-2663},
abstract = {Neurodegenerative diseases are a growing cause of disability worldwide, particularly as populations age. Although these disorders differ in etiology and clinical presentation, advances in genetics, neuropathology, and biomarker research have identified shared disturbances in protein homeostasis, mitochondrial function, and immune regulation. These processes may contribute to selective neuronal vulnerability and neural circuit dysfunction. These findings are refining disease classification and diagnosis, yet effective disease-modifying therapies remain limited. Disease-specific abnormalities remain essential to clinical interpretation and treatment selection. Existing reviews often focus on individual disorders or isolated mechanisms, leaving the links between shared biology and disease-specific phenotypes insufficiently clear. We synthesize evidence on the epidemiology, risk factors, classification, and pathophysiology of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, frontotemporal dementia, Friedreich's ataxia, and multiple sclerosis. We compare their clinical manifestations and diagnostic approaches, including the evolving role of biomarkers, and critically assess established and emerging therapies. By distinguishing shared mechanisms from disease-specific abnormalities, we identify key translational gaps and explore how common biological disturbances may lead to distinct clinical trajectories. This cross-disease perspective may inform diagnostic reasoning, treatment development, and future comparative research.},
}

@article {pmid42898978,
year = {2026},
author = {Peng, S and Wang, L and Ouyang, J and Liu, R},
title = {The Role of Astrocytes in the Inflammatory Response in Neurodiseases.},
journal = {MedComm},
volume = {7},
number = {11},
pages = {e71069},
pmid = {42898978},
issn = {2688-2663},
abstract = {Astrocytes have emerged as central regulators of neuroinflammation, extending far beyond their traditional roles as structural and metabolic support cells. In neurological disorders, astrocytes undergo reactive remodeling that encompasses morphological, transcriptional, metabolic, and functional changes. Rather than fitting into a fixed A1/A2 dichotomy, reactive astrocytes exist along a disease-, region-, and stage-dependent continuum shaped by local pathology and intercellular crosstalk. This review summarizes how astrocytes contribute to neuroinflammatory processes in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, central nervous system injury, infection, multiple sclerosis, epilepsy, and autism spectrum disorder. We highlight convergent mechanisms, including cytokine and chemokine release, complement activation, glutamate and ion homeostasis disruption, oxidative stress, metabolic reprogramming, and blood-brain barrier regulation, while emphasizing disease-specific astrocytic programs. We further discuss astrocyte interactions with microglia, neurons, oligodendrocytes, endothelial cells, and peripheral immune cells, as well as key regulatory pathways, epigenetic remodeling, and lipid-dependent metabolic signaling. Finally, we evaluate current and emerging astrocyte-targeted therapeutic strategies, including metabolic modulation, receptor targeting, gene editing, nanodelivery, and gut-brain axis interventions. Defining functionally validated astrocyte states and developing biomarker-guided, stage-adaptive therapies may enable more precise intervention in neuroinflammatory and neurodegenerative diseases.},
}

@article {pmid42906263,
year = {2026},
author = {Hawas, Y and Abo-Elnour, DE and Al-Hawari, NEM and Gahlan, S and Winkelman, JW},
title = {Restless legs syndrome and other neurological disorders: A systematic-narrative hybrid literature review with exploratory meta-analysis.},
journal = {Sleep medicine reviews},
volume = {90},
number = {},
pages = {102390},
doi = {10.1016/j.smrv.2026.102390},
pmid = {42906263},
issn = {1532-2955},
abstract = {Restless legs syndrome (RLS) is a sleep-related sensorimotor disorder affecting approximately 3% of adults worldwide. This review aims to synthesize current evidence on associations between RLS and major neurological conditions, provide an exploratory quantitative synthesis summarizing association patterns and heterogeneity, and identify priority mechanistic and clinical research gaps. Databases were searched from inception until August 2026. In our exploratory synthesis of 119 unique studies, RLS was significantly associated with Parkinson's disease (case-control OR 3.22, 95% CI 2.35-4.41; cohort RR 1.74, 95% CI 1.02-2.95), multiple sclerosis (OR 4.04, 95% CI 3.26-5.00), neuromyelitis optica spectrum disorder (OR 2.91, 95% CI 1.45-5.84), migraine or headache disorders (forward OR 2.72, 95% CI 2.19-3.38; reverse adjusted OR 1.53, 95% CI 1.36-1.73), peripheral neuropathy (OR 3.82, 95% CI 2.49-5.83), epilepsy (OR 2.11, 95% CI 1.58-2.82), and amyotrophic lateral sclerosis (OR 7.69, 95% CI 2.74-21.59). This work is an evidence-mapping review with exploratory pooling and is not intended as a definitive evidence synthesis. RLS is likely associated with neurodegenerative and other specific neurological conditions. Recognition of these associations may support earlier identification of comorbid conditions and targeted management strategies. However, the current evidence remains observational and heterogeneous.},
}

@article {pmid42913489,
year = {2026},
author = {Huang, J and Zhang, S and Zhang, D and Yang, T and Li, C and He, M and Wang, J and Song, T and Wang, X and Lu, Y and Kong, Q and Tan, J and Zhang, J},
title = {Liquid-liquid phase separation in neurodegenerative diseases: Mechanisms, pathological transitions, and therapeutic opportunities.},
journal = {Science progress},
volume = {109},
number = {4},
pages = {368504261499190},
doi = {10.1177/00368504261499190},
pmid = {42913489},
issn = {2047-7163},
mesh = {Humans ; *Neurodegenerative Diseases/metabolism/pathology/genetics/therapy ; Phase Separation ; Animals ; Protein Aggregation, Pathological/metabolism ; Amyloid beta-Peptides/metabolism/chemistry/genetics ; DNA-Binding Proteins/metabolism/genetics ; Huntingtin Protein/genetics/metabolism ; tau Proteins/metabolism/genetics/chemistry ; alpha-Synuclein/metabolism/genetics/chemistry ; RNA-Binding Protein FUS/metabolism/genetics ; Biomolecular Condensates/metabolism ; },
abstract = {Liquid-liquid phase separation (LLPS) provides a biophysical framework for understanding biomolecular organization, yet its pathological relevance in neurodegeneration remains incompletely resolved. In this narrative review, we critically synthesize current evidence on LLPS in Huntington's disease, Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis, focusing on mutant huntingtin, α-synuclein, amyloid-β, tau, TDP-43, and FUS. We first outline the molecular principles-including intrinsic disorder, multivalent interactions, and environmental sensitivity-that govern their phase behavior. We then examine how dynamic condensates may, under specific cellular contexts, transition toward less reversible oligomeric, gel-like, or solid assemblies, integrating evidence from in vitro, cellular, and in vivo studies. Importantly, current evidence does not support LLPS as a universal or obligatory precursor of pathological aggregation; rather, its biological consequences appear to depend on condensate composition, material properties, subcellular localization, and proteostasis capacity, while direct demonstration of disease-relevant condensates in vivo remains limited. We further discuss whether aberrant LLPS represents a cause, consequence, or context-dependent component of neurodegeneration and highlight emerging strategies that modulate condensate formation, maturation, or clearance while preserving physiological functions. Overall, this review defines both the mechanistic potential and current limitations of the LLPS framework and identifies key questions that must be addressed before pathological phase-state modulation can become a clinically actionable therapeutic strategy.},
}

Humans
*Neurodegenerative Diseases/metabolism/pathology/genetics/therapy
Phase Separation
Animals
Protein Aggregation, Pathological/metabolism
Amyloid beta-Peptides/metabolism/chemistry/genetics
DNA-Binding Proteins/metabolism/genetics
Huntingtin Protein/genetics/metabolism
tau Proteins/metabolism/genetics/chemistry
alpha-Synuclein/metabolism/genetics/chemistry
RNA-Binding Protein FUS/metabolism/genetics
Biomolecular Condensates/metabolism

@article {pmid42916114,
year = {2026},
author = {Milardi, D and Han, J and Lee, HJ and Ding, F and Miller, Y and Faller, P and Bush, AI and Crouch, PJ and Finkelstein, DI and Double, KL and Jeremic, A and Lim, MH and Ramamoorthy, A},
title = {Metal Ions and Protein Aggregation: Unraveling Molecular Interactions and Theranostic Prospects in Proteinopathies.},
journal = {Chemical reviews},
volume = {126},
number = {18},
pages = {10249-10333},
doi = {10.1021/acs.chemrev.5c00420},
pmid = {42916114},
issn = {1520-6890},
support = {R01AG048934/AG/NIA NIH HHS/United States ; R35GM13973/GM/NIGMS NIH HHS/United States ; R35GM145409/GM/NIGMS NIH HHS/United States ; R01DK132214/DK/NIDDK NIH HHS/United States ; NA//Florida State University/ ; NA//National High Magnetic Field Laboratory/ ; 2022PAAYZE//NextGenerationEU/ ; CUP: B53D23016440006//NextGenerationEU/ ; DP230101031//Australian Research Council/ ; GNT1194028//National Health and Medical Research Council/ ; GNT2019931//National Health and Medical Research Council/ ; RS-2022-NR070709//National Research Foundation of Korea/ ; RS-2022-NR073879//National Research Foundation of Korea/ ; RS-2024-00353015//National Research Foundation of Korea/ ; RS-2024-00411134//National Research Foundation of Korea/ ; MRF2007656//Medical Research Future Fund/ ; },
mesh = {Humans ; *Protein Aggregation, Pathological/metabolism/drug therapy ; *Neurodegenerative Diseases/metabolism/drug therapy ; *Metals/chemistry/metabolism ; Animals ; Protein Aggregates ; },
abstract = {Protein aggregation is a pathological process associated with several human diseases termed proteinopathies, including neurodegenerative and metabolic disorders such as Alzheimer's disease, Parkinson's disease, type II diabetes, amyotrophic lateral sclerosis, and Huntington's disease. In these conditions, specific proteins misfold and accumulate into insoluble aggregates, disrupting normal cellular function and contributing to disease progression. Many studies have investigated the molecular mechanisms that underlie the aggregation pathways, the structure of aggregates, such as oligomeric intermediates and fibrils, and their cellular toxicity. Studies have also investigated the effects of cofactors like metals, lipids, other amyloid proteins, and small molecules. Recent research has increasingly emphasized the critical roles of metal ions such as copper (Cu), zinc (Zn), iron (Fe), and manganese (Mn) in amyloid aggregation and toxicity. Alterations in metal ion transport, binding, or redox activity have been linked to the onset and progression of several amyloid-associated diseases. These metal ions can interact directly with amyloidogenic proteins, influencing their structural conformation, aggregation kinetics, and propensity to form toxic oligomers. This review aims to advance our understanding of how the regulation of metal ions within cells and their dysfunction contribute to the accumulation of harmful proteins, which is a key factor in proteinopathies. By examining the interactions between metal ions and key amyloidogenic proteins─including amyloid-β (Aβ), α-synuclein, tau, superoxide dismutase 1 (SOD1), human islet amyloid polypeptide (hIAPP), and insulin─we highlight both common and unique pathways through which metal ions influence protein aggregation. Additionally, this review explores the impact of metal ions on protein clearance mechanisms, such as autophagy and the ubiquitin-proteasome system, as well as emerging theranostic strategies. These include metal chelation therapies, metal-based imaging agents, and multifunctional compounds designed to restore metal balance while preventing aggregation and toxicity. By integrating biochemical, cellular, and therapeutic insights, this review contributes to a deeper understanding of the metallobiology of proteinopathies and supports the development of novel diagnostic and treatment approaches targeting metal-protein interactions.},
}

Humans
*Protein Aggregation, Pathological/metabolism/drug therapy
*Neurodegenerative Diseases/metabolism/drug therapy
*Metals/chemistry/metabolism
Animals
Protein Aggregates

@article {pmid42918320,
year = {2026},
author = {Nasb, M and Yang, D and Malik, TH and Xu, D and Dayoub, L and Zhou, J and Zhao, Y},
title = {State transitions in amyotrophic lateral sclerosis: mechanistic convergence and biomarker-guided stratification.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2026.10.036},
pmid = {42918320},
issn = {1873-7544},
abstract = {BACKGROUND: Biological heterogeneity is a major obstacle to therapeutic development in amyotrophic lateral sclerosis (ALS). Cross-sectional pathway labels do not show whether a mechanism is active or treatment-relevant in an individual patient.

METHODS: We conducted a structured critical narrative review informed by the Scale for the Assessment of Narrative Review Articles. MEDLINE, Embase, PubMed, and CENTRAL were searched for English-language literature published from 1 January 2015 to 7 August 2026; seminal earlier studies were identified by citation tracking. Human genetic, pathological, longitudinal biomarker, multi-omic, imaging, neurophysiological, and interventional evidence was prioritized. Evidence was appraised by human proximity, temporality, replication, mechanistic specificity, and treatment relevance.

RESULTS: Evidence supports interacting RNA/proteostasis, nucleocytoplasmic-transport, glial-inflammatory, and energetic-metabolic processes, but current evidence does not yet support the use of any candidate state for individual treatment assignment. The most mature temporal example is loss of TDP-43 splicing repression before neurofilament elevation in genetically at-risk individuals. Nucleocytoplasmic-transport evidence is strongest in C9orf72 disease; inflammatory and metabolic signals are confounded by disease burden and systemic illness; and the gut-brain axis remains a context-dependent amplifier. We propose prespecified transition rules, evidence grades, and biomarker-by-treatment interaction tests.

CONCLUSIONS: A state-transition model becomes clinically useful when longitudinal measurements add value beyond clinical predictors and injury markers and prospectively identify differential treatment benefit.},
}

@article {pmid42918387,
year = {2026},
author = {Verma, A and Goyal, A and Agrawal, N and Yadav, HN},
title = {Cellular senescence in ageing and neurodegenerative disorders: Molecular mechanisms, biomarkers, and therapeutic strategies.},
journal = {Progress in neuro-psychopharmacology & biological psychiatry},
volume = {},
number = {},
pages = {111985},
doi = {10.1016/j.pnpbp.2026.111985},
pmid = {42918387},
issn = {1878-4216},
abstract = {Cellular senescence has been increasingly associated with neurodegenerative disorders, potentially linking ageing-related cellular impairment with mitochondrial dysfunction, chronic inflammation, and disrupted intercellular signalling. The present study aims to explore the increasing relevance of cellular senescence among key cell types, including neurons, astrocytes, neural progenitor cells, microglia and oligodendrocyte-lineage cells across neurodegenerative ailments such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and multiple sclerosis. This review discusses the findings of pre-clinical and clinical studies which suggest that senescence-associated features may contribute to neurodegeneration. Further, it provides an overview of the biomarkers used in the identification of senescence in the CNS. Also, the review examines senotherapeutic treatment approaches, highlighting their actions on different CNS cell types and the growing clinical evidence. It also points out the challenges in translating these approaches to clinical application, such as targeting specific cell types and the lack of suitable biomarkers. Collectively, present findings suggest that senescence-associated alterations may contribute to neurodegeneration, although their effects appear to vary across cell types and diseases.},
}

@article {pmid42778416,
year = {2026},
author = {Fujino, Y and Nagai, Y},
title = {[Regulatory mechanisms of repeat-associated non-AUG translation: unveiling a novel molecular pathomechanism in repeat expansion diseases].},
journal = {Rinsho shinkeigaku = Clinical neurology},
volume = {66},
number = {10},
pages = {691-700},
doi = {10.5692/clinicalneurol.cn-002278},
pmid = {42778416},
issn = {1882-0654},
mesh = {Animals ; Humans ; *Protein Biosynthesis/genetics ; Disease Models, Animal ; Codon, Initiator/genetics ; *Neuromuscular Diseases/genetics ; Drosophila ; Molecular Targeted Therapy ; *Trinucleotide Repeat Expansion/genetics ; *DNA Repeat Expansion/genetics ; Untranslated Regions/genetics ; },
abstract = {The expansion of genomic repeat sequences can cause more than 50 hereditary neuromuscular diseases, collectively referred to as repeat expansion diseases. In noncoding repeat expansion diseases caused by the expanded repeat sequences in the untranslated regions, repeat RNAs transcribed from the mutant genes can undergo repeat-associated non-AUG (RAN) translation despite lacking canonical AUG initiation codons, leading to the production of toxic repeat polypeptides that contribute to neurodegeneration. RAN translation has emerged as a promising therapeutic target for noncoding repeat expansion diseases; however, its regulatory mechanisms remain unclear. In this review, the characteristics of RAN translation and its roles in neuromuscular pathogenesis are overviewed. In addition, our research efforts for elucidating the regulatory mechanisms of RAN translation using Drosophila disease models are introduced.},
}

Animals
Humans
*Protein Biosynthesis/genetics
Disease Models, Animal
Codon, Initiator/genetics
*Neuromuscular Diseases/genetics
Drosophila
Molecular Targeted Therapy
*Trinucleotide Repeat Expansion/genetics
*DNA Repeat Expansion/genetics
Untranslated Regions/genetics

@article {pmid42895667,
year = {2026},
author = {Abu-Omar, K and Tcymbal, A and Messing, S and Gelius, P},
title = {[Physical activity and physical activity promotion among people with a migration background in Germany].},
journal = {Bundesgesundheitsblatt, Gesundheitsforschung, Gesundheitsschutz},
volume = {},
number = {},
pages = {},
pmid = {42895667},
issn = {1437-1588},
abstract = {Health equity has gained increasing importance in physical activity and health promotion and is firmly established as an important goal both internationally and in Germany. As social inequalities and multiple disadvantages influence physical activity behavior, population groups facing particular barriers to access-including people with a migration background-should receive greater consideration in physical activity promotion. This article provides an overview of the current state of research on physical activity and physical activity promotion among people with a migration background in Germany.Representative data indicate that people with a migration background are less physically active than people without a migration background. Key barriers reported include limited financial resources, language barriers, restricted opportunities for physical activity, and cultural factors. Different forms of social disadvantage, for example those related to gender, socioeconomic status, and migration background, may intersect and reinforce barriers to access. Using the project "Bewegung als Investition in Gesundheit" (BIG; "Physical Activity as an Investment in Health") as an example, this article illustrates how participatory and target-group-specific interventions can be used to reach, in particular, women with a migration background.In addition to participatory and target-group-specific interventions, equitable physical activity promotion requires structural conditions that facilitate access to opportunities for physical activity. The sustainable implementation and scaling-up of such interventions can contribute to reducing barriers to access and promoting health equity.},
}

@article {pmid41795667,
year = {2026},
author = {Burgess, A and Allen, O and Barkhaus, P and Barnes, B and Benatar, M and Bertorini, T and Bowser, R and Mascias Cadavid, J and Carter, GT and Cudkowicz, M and Denson, K and Dyckman, K and Elsharif, B and Feldman, E and Foucher, J and Fullum, T and Glass, J and Helmold, B and Jackson, C and Jhooty, S and Leday, A and Mallon, E and Mcdermott, C and Olby, N and Ostrow, L and Pattee, G and Pioro, E and Ratner, D and Sang, H and Tito, E and Vieira, F and Wicks, P and Bedlack, R and Gelevski, D},
title = {ALS untangled #83: clenbuterol.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {27},
number = {7-8},
pages = {949-956},
doi = {10.1080/21678421.2026.2638588},
pmid = {41795667},
issn = {2167-9223},
mesh = {*Clenbuterol/therapeutic use/pharmacology ; Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Animals ; *Adrenergic beta-2 Receptor Agonists/therapeutic use/pharmacology ; },
abstract = {ALS Untangled reviews alternative and off-label treatments for people living with amyotrophic lateral sclerosis (PALS). Here we review clenbuterol, a β-2 adrenergic agonist, as a potential treatment for amyotrophic lateral sclerosis (ALS). Clenbuterol has biological effects that could be relevant to the pathophysiology of ALS such as inducing muscle hypertrophy, improving mitochondrial function, and reducing neuroinflammation. Two studies in mouse models of motor neuron disease and two open label trials suggest possible benefits. However these have methodological flaws which limit interpretation. Clenbuterol can have an array of side effects, some severe. Drop-outs due to side effects were very common in one of the ALS trials and in a separate expanded access program. Based on this information, we cannot currently endorse clenbuterol as an ALS treatment, but we do hope to see further studies of it, or another long acting β-2 adrenergic agonist in people with ALS.},
}

*Clenbuterol/therapeutic use/pharmacology
Humans
*Amyotrophic Lateral Sclerosis/drug therapy
Animals
*Adrenergic beta-2 Receptor Agonists/therapeutic use/pharmacology

@article {pmid41989758,
year = {2026},
author = {Ahmed, M and Volkening, K and Mclellan, C and Shoesmith, C and Balci, TB and Strong, MJ},
title = {Emerging strategies for interpreting variants of uncertain significance (VUS) in amyotrophic lateral sclerosis.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {27},
number = {7-8},
pages = {793-807},
doi = {10.1080/21678421.2026.2655734},
pmid = {41989758},
issn = {2167-9223},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/diagnosis ; *Genetic Testing/methods ; *Genetic Predisposition to Disease/genetics ; *Genetic Variation/genetics ; *Frontotemporal Dementia/genetics ; },
abstract = {As the use of genetic testing for neurological diseases increases exponentially, interpreting variants of uncertain significance (VUS) has become a challenging problem. Nowhere has this become more evident than in amyotrophic lateral sclerosis (ALS) and the frontotemporal dementias (FTDs), both of which are complex heterogeneous disorders in which an increasing array of disease-causative and modifying genetic variants are observed. Moreover, while traditionally identified as distinct clinical syndromes, ALS and FTD are increasingly recognized to exist along a spectrum of clinical syndromes (termed the frontotemporal spectrum disorders of ALS; ALS-FTSD) with shared genetic risk. While VUS are generally not used in clinic for decision-making or counseling given their obvious limitations in being medically actionable, their correct interpretation is dynamic and rapidly evolving. VUS are increasingly the subject of intensive study as potential determinants of biological outcomes. It is timely therefore to review the current state of VUS interpretation and to critically evaluate how this can be applied to enhance both patient care and treatment decisions in the broader context of neurological disorders and more specifically in the context of ALS and ALS-FTSD. In doing so, we also explore the evolving challenge of defining pathogenicity of oligogenic inheritance in the context of multiple VUS detection in a single individual using an illustrative case example.},
}

Humans
*Amyotrophic Lateral Sclerosis/genetics/diagnosis
*Genetic Testing/methods
*Genetic Predisposition to Disease/genetics
*Genetic Variation/genetics
*Frontotemporal Dementia/genetics

@article {pmid42893382,
year = {2026},
author = {Pollock, D and Shrestha, N and Facchin-Young, SC and Fragkoudi, A and Day-Sharman, AM and Bulto, LN and Bond, M and Stern, C and Barker, TH and Hasanoff, S and Holland, G and Semendric, I and Stollery, L and Sharma, S and Viswanath Harish, Y and Schubert, C and Giles, L and Beasley-Hall, J and Merlin, T and Labra, J and Vucic, S and Hunt, T and Munn, Z},
title = {Mapping care interventions for people living with motor neurone disease: a living evidence and gap map.},
journal = {Neurodegenerative disease management},
volume = {},
number = {},
pages = {1-12},
doi = {10.1080/17582024.2026.2749397},
pmid = {42893382},
issn = {1758-2032},
abstract = {Motor neurone disease (MND) is a debilitating, life-limiting neurodegenerative disease that has no cure. Caring for a person living with MND requires a multidisciplinary team delivering interventions to address symptoms. We aimed to map evidence supporting care of those living with MND. Evidence and gap maps (EGMs) were developed according to Campbell and JBI guidance for scoping reviews. Databases searched included CENTRAL, MEDLINE, EMBASE, and PsycINFO with no date restriction. Articles describing care interventions for people living with MND, carers, asymptomatic genetic carriers, family, friends, and healthcare professionals were included. 2390 reports were drawn from 1594 articles that were included across five EGMs, supportive and symptom management (n = 673 articles), pharmacological (n = 592), models of care (n = 196), medical and clinical interventions (n = 185), and technology and equipment (n = 91). Interventions primarily addressed people who are living with MND (n = 1732). No articles were identified specifically concerning First Nations Peoples, Culturally and Linguistically Diverse Peoples, or those living in remote, rural or regional areas. MND care interventions are diverse. Further research is needed to understand options for Culturally and Linguistically Diverse Peoples, First Nations Peoples, and those living in rural, regional, and remote communities.},
}

@article {pmid42892517,
year = {2026},
author = {Xu, Z and Chen, X and Yi, W},
title = {Cryo-EM advances in TDP-43 amyloid fibrils structure determination.},
journal = {Neurobiology of disease},
volume = {},
number = {},
pages = {107659},
doi = {10.1016/j.nbd.2026.107659},
pmid = {42892517},
issn = {1095-953X},
abstract = {TAR DNA-binding protein 43 (TDP-43) is a DNA/RNA-binding protein whose pathological aggregation characterizes a spectrum of neurodegenerative disorders known as TDP-43 proteinopathies, including amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), and chronic traumatic encephalopathy (CTE). Recent breakthroughs in cryo-electron microscopy (cryo-EM) have revolutionized our understanding of these diseases by resolving the atomic structures of TDP-43 amyloid fibrils. These structural insights have been pivotal in elucidating the transition from functional liquid-liquid phase separation (LLPS) to irreversible solid-state aggregation. This review synthesizes key cryo-EM findings from 2019 to 2026, encompassing fibrils formed by the full-length low-complexity domain, disease-relevant core fragments, and filaments extracted directly from patient tissues, as well as the pathological implications of distinct structural polymorphs. These findings not only deepen our understanding of the brain science aspects of the pathogenesis of TDP-43 proteinopathies, but also provide an important structural basis for the development of specific conformational diagnostic methods and targeted therapeutic drugs.},
}

@article {pmid42883328,
year = {2026},
author = {Garbarek, J and Hys, O and Woźniak, A and Szewczyk-Golec, K and Nuszkiewicz, J},
title = {Bee-Derived Products in Neurodegenerative Diseases: Bioactive Constituents, Redox-Modulating Mechanisms, Evidence, and Translational Perspectives.},
journal = {Molecules (Basel, Switzerland)},
volume = {31},
number = {19},
pages = {},
doi = {10.3390/molecules31193564},
pmid = {42883328},
issn = {1420-3049},
mesh = {Humans ; Animals ; *Neurodegenerative Diseases/drug therapy/metabolism ; Oxidation-Reduction/drug effects ; Antioxidants/pharmacology/chemistry/therapeutic use ; *Neuroprotective Agents/pharmacology/chemistry/therapeutic use ; Bees/chemistry ; Propolis/chemistry/therapeutic use ; Oxidative Stress/drug effects ; Royal Jelly ; *Bee Venoms/chemistry/therapeutic use/pharmacology ; Anti-Inflammatory Agents/pharmacology/chemistry/therapeutic use ; Signal Transduction/drug effects ; Honey/analysis ; },
abstract = {Oxidative stress, mitochondrial dysfunction, and chronic neuroinflammation are closely interconnected processes involved in the pathogenesis and progression of neurodegenerative diseases. Bee-derived products, including honey, propolis, royal jelly, bee pollen, bee bread, and bee venom, contain diverse bioactive constituents with antioxidant, anti-inflammatory, immunomodulatory, and redox-modulating properties. This narrative review summarizes the major bioactive compounds present in bee-derived products and evaluates their potential relevance to neuroprotection. Particular attention is given to mechanisms involving activation of the Nrf2/ARE antioxidant response, inhibition of NF-κB-dependent inflammatory signaling, modulation of the NLRP3 inflammasome, mitochondrial protection, regulation of apoptosis, and maintenance of proteostasis. Available evidence from cellular and animal models, together with the limited clinical data, is discussed primarily in the context of Alzheimer's and Parkinson's diseases, with additional consideration of amyotrophic lateral sclerosis and other neurodegenerative or neuroinflammatory conditions. Although several bee-derived products and isolated constituents show promising biological effects, their therapeutic translation remains limited by variable chemical composition, insufficient standardization, low or uncertain bioavailability, limited evidence of central nervous system exposure, and safety concerns. Further mechanistic, pharmacokinetic, and well-controlled clinical studies are therefore required before their potential neuroprotective applications can be reliably established.},
}

Humans
Animals
*Neurodegenerative Diseases/drug therapy/metabolism
Oxidation-Reduction/drug effects
Antioxidants/pharmacology/chemistry/therapeutic use
*Neuroprotective Agents/pharmacology/chemistry/therapeutic use
Bees/chemistry
Propolis/chemistry/therapeutic use
Oxidative Stress/drug effects
Royal Jelly
*Bee Venoms/chemistry/therapeutic use/pharmacology
Anti-Inflammatory Agents/pharmacology/chemistry/therapeutic use
Signal Transduction/drug effects
Honey/analysis

@article {pmid42883433,
year = {2026},
author = {Li, P and Qi, ZM and Wu, JZ and Liu, J and Yu, P},
title = {Targeting Ferroptosis in Neurodegenerative Diseases: Therapeutic Potential and Mechanistic Insights of Traditional Chinese Medicine.},
journal = {Biology},
volume = {15},
number = {19},
pages = {},
doi = {10.3390/biology15191760},
pmid = {42883433},
issn = {2079-7737},
support = {NO.20250204060YY//Jilin Province Science and Technology Department/ ; },
abstract = {Neurodegenerative diseases (NDs), including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and multiple sclerosis, are characterized by progressive and irreversible neuronal loss, whereas current treatments remain largely symptomatic. Ferroptosis is an iron-dependent form of regulated cell death whose execution is defined by iron-enabled phospholipid peroxidation and failure of cellular ferroptosis-defense systems. Mitochondrial metabolism can modify ferroptosis susceptibility, but its contribution varies with cell type and initiating stimulus. Converging evidence implicates ferroptosis in multiple NDs, in which affected regions commonly show iron accumulation, glutathione depletion, and increased lipid peroxidation. With their multi-component and multi-target properties, traditional Chinese medicine (TCM) interventions may modulate several nodes in this network. This review summarizes the core execution and defense mechanisms of ferroptosis, evaluates their roles in major NDs, and critically appraises bioactive herbal compounds, compound formulas, acupuncture, electroacupuncture, and moxibustion. The reported interventions mainly engage the Nrf2/GPX4 antioxidant axis, TFR1/FPN1/FTH1/NCOA4-mediated iron handling, ACSL4-dependent lipid peroxidation, and GPX4-independent defense systems. Because most studies are preclinical and many infer ferroptosis from non-specific markers, the evidence is graded here as direct, supportive, indirect, mixed, or complementary. Translation will require standardized formulations, causal ferroptosis validation, pharmacokinetic and brain-exposure data, validated human biomarkers, and rigorously designed clinical trials.},
}

@article {pmid42880848,
year = {2026},
author = {Martin, LJ},
title = {DNA methylation in motor neuron biology and epigeneticopathy in amyotrophic lateral sclerosis.},
journal = {Handbook of clinical neurology},
volume = {219},
number = {},
pages = {381-397},
doi = {10.1016/B978-0-443-19043-8.00014-1},
pmid = {42880848},
issn = {0072-9752},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; *Motor Neurons/metabolism/pathology/physiology ; *DNA Methylation/genetics/physiology ; Animals ; *Epigenesis, Genetic/genetics/physiology ; },
abstract = {Amyotrophic lateral sclerosis (ALS), the 3rd most frequent neurodegenerative disease, is fatal. Skeletal muscles, neuromuscular junctions, and motor neurons in the cerebral cortex, brainstem, and spinal cord that control swallowing, breathing, and movement degenerate, causing paralysis, respiratory arrest, and death. Clinically meaningful disease mechanisms are unknown, and no effective therapies are available. ALS is a polygenic heterogeneous disease seen in 5%-10% of patients as inherited, but most patients have no inheritance pattern. ALS appears to manifest as a complex interplay between many genes in multiple tissues, individual lifestyle, the environment, and metabolism. Monozygotic twin and triplet studies of ALS suggest that epigenetic mechanisms could be involved in the pathogenesis because discordance is seen. Epigenetic anomalies involving DNA and RNA methylation occur in human ALS. Cell and animal models show that motor neuron development and degeneration can be regulated by DNA methylation. This chapter summarizes the DNA and RNA epigenetic anomalies that are prominent in human ALS and models of ALS, concluding with the suggestion that they are promising therapeutic targets with small molecules.},
}

Humans
*Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism
*Motor Neurons/metabolism/pathology/physiology
*DNA Methylation/genetics/physiology
Animals
*Epigenesis, Genetic/genetics/physiology

@article {pmid42881132,
year = {2026},
author = {Trucco, AP and Camino, J and Bedford, J and Mioshi, E},
title = {Interventions to support informal carers managing behavioral symptoms in frontotemporal lobar degeneration: a scoping review.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-13},
doi = {10.1080/21678421.2026.2741037},
pmid = {42881132},
issn = {2167-9223},
abstract = {OBJECTIVE: Informal carers of people living with frontotemporal lobar degeneration (FTLD) face significant challenges in managing complex behavioral symptoms, yet disease specific support remains limited. This scoping review explored non-pharmacological interventions developed to support this carer population.

METHODS: Database searches were conducted across Medline, APA PsycINFO, CINAHL, ERIC, E-Journals, and Scopus from January 2011 to November 2025, supplemented by hand searching, identifying nine included studies.

RESULTS: Interventions broadly comprised occupational therapy-based activity programmes, psychoeducational approaches, and web-based self-management tools. The majority of studies were feasibility or acceptability studies, with findings generally positive; however, behavioral symptoms were inconsistently reported, and sample sizes were small, highlighting that evidence remains at an early stage.

CONCLUSION: Despite the promising nature of existing approaches, structured implementation of non-pharmacological interventions to support informal carers manage behavioral symtoms into clinical practice remains absent. Translating feasible and acceptable interventions into accessible, disease-specific support for carers of people living with FTLD is urgently needed.},
}

@article {pmid42882466,
year = {2026},
author = {Burdman, G and Hanna, M and Arias, AY and Vashist, A and Lakshmana, MK},
title = {Human iPSC-Derived Brain Cells, Organoids, and Organoids-on-Chips: Advancing Neurological Disease Modeling to Improve Clinical Outcome.},
journal = {Cells},
volume = {15},
number = {19},
pages = {},
doi = {10.3390/cells15191768},
pmid = {42882466},
issn = {2073-4409},
support = {1R21DA060111, 1R61AG086971, R03AG08475//National Institute of Health (NIH)/ ; },
mesh = {Humans ; *Induced Pluripotent Stem Cells/cytology/metabolism ; *Brain/pathology/cytology ; *Organoids/pathology/cytology ; *Nervous System Diseases/pathology ; Animals ; Microphysiological Systems ; Neurons/pathology ; Models, Biological ; },
abstract = {Neurological disorders are the leading cause of overall disease and disability worldwide, affecting more than 3.4 billion people globally and over 180 million Americans. Yet there are no curative treatments available for any of the cardinal neurological diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) and Huntington's disease (HD). Many compounds that demonstrate excellent activity in preclinical models fail in clinical trials. The most compelling reason for this failure is attributed to inherent limitations of rodent models that fail to replicate complex human biology. The transformation of patient-derived somatic cells into induced pluripotent stem cells (iPSCs) that can become functional human neurons is an emerging technology that is expected to revolutionize medical treatments and personal medicine. Here, we review the available evidence for the efficacy of iPSC-derived neurons, organoids, assembloids and organ-on-chip in models of AD, PD, ALS-FTD and HD. We focus on how these human-relevant iPSC-derived brain cells are crucial for understanding neurological disease pathogenesis and accelerating drug discovery. We also discuss the current limitations of this technology and how alternative models such as induced neurons (iNs) are generated by directly reprogramming fibroblasts that preserve age-associated epigenetic signatures and may serve as better models for neurological disorders.},
}

Humans
*Induced Pluripotent Stem Cells/cytology/metabolism
*Brain/pathology/cytology
*Organoids/pathology/cytology
*Nervous System Diseases/pathology
Animals
Microphysiological Systems
Neurons/pathology
Models, Biological

@article {pmid42882496,
year = {2026},
author = {Morrone, M and Valori, CF and Brambilla, L and Rossi, D},
title = {Motor Neuron Disease in a Dish: The Power of Human Induced Pluripotent Stem Cell-Derived Spinal Motor Neurons and Glial Cells.},
journal = {Cells},
volume = {15},
number = {19},
pages = {},
doi = {10.3390/cells15191798},
pmid = {42882496},
issn = {2073-4409},
support = {JPND2022-DC4MND//Ministry of Health/ ; },
mesh = {Humans ; *Induced Pluripotent Stem Cells/metabolism/cytology/pathology ; *Motor Neurons/pathology/metabolism ; *Neuroglia/pathology/metabolism ; *Motor Neuron Disease/pathology ; *Amyotrophic Lateral Sclerosis/pathology ; Animals ; Cell Differentiation ; Astrocytes/pathology/metabolism ; },
abstract = {Induced pluripotent stem cells (iPSCs) have revolutionized disease modelling by providing unprecedented opportunities to investigate complex human disorders. Among others, Amyotrophic Lateral Sclerosis (ALS), the most common adult-onset motor neuron disease, clearly embodies this complexity. This disorder remains particularly challenging not only because of its marked clinical and molecular heterogeneity but also as a consequence of the composite interactions between motor neurons and the neighboring non-neuronal cells, especially astrocytes, which contribute to disease progression. The ability to generate patient-specific spinal motor neurons and astrocytes from human iPSCs has enabled the development of in vitro models that recapitulate key pathological features of ALS, offering valuable platforms to investigate disease mechanisms, to identify therapeutic targets, and to support personalized medicine approaches. In this review, we summarize current iPSC-based strategies for modelling ALS, highlighting their applications in studying disease physiopathology and drug development. In addition, advanced human iPSC-derived technologies, including organoids and organ-on-a-chip systems, are discussed highlighting their potential, current limitations, and future perspectives.},
}

Humans
*Induced Pluripotent Stem Cells/metabolism/cytology/pathology
*Motor Neurons/pathology/metabolism
*Neuroglia/pathology/metabolism
*Motor Neuron Disease/pathology
*Amyotrophic Lateral Sclerosis/pathology
Animals
Cell Differentiation
Astrocytes/pathology/metabolism

@article {pmid42872064,
year = {2026},
author = {Cai, W and Yi, Y and Zeng, R and Yin, Y and Zhao, J and Zhang, J and Fu, G and Xu, H},
title = {HMGB1 functional plasticity in neurodegenerative diseases and its translational implications.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1928641},
pmid = {42872064},
issn = {1664-3224},
mesh = {Humans ; *HMGB1 Protein/metabolism/genetics ; *Neurodegenerative Diseases/metabolism ; Animals ; Translational Research, Biomedical ; Signal Transduction ; Alarmins/metabolism ; Biomarkers ; },
abstract = {High mobility group box 1 (HMGB1) is a chromatin-associated protein that can be redistributed and released during cellular stress, when it acts as an extracellular alarmin within the broader family of damage-associated molecular patterns (DAMPs). Its functions depend on subcellular localization, redox and post-translational modification state, cellular source, mode of release, and molecular partners. This critical narrative review examines how these variables shape HMGB1 biology in Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), spinocerebellar ataxias (SCAs), frontotemporal dementia (FTD), and related disorders, and considers their implications for biomarker and therapeutic development. Intracellular HMGB1 contributes to chromatin organization, DNA repair, mitochondrial genome maintenance, and proteostasis. After redistribution and release, extracellular HMGB1 signals through receptors including the receptor for advanced glycation end products (RAGE) and Toll-like receptor 4 (TLR4), interacts with disease-associated proteins, and links proteostatic stress with glial activation, neuronal dysfunction, and blood-brain barrier impairment. Across disease models, two recurrent patterns emerge: loss or sequestration of intracellular HMGB1 in models of polyglutamine disorders, including HD and SCAs, and extracellular HMGB1 signaling as a progression-associated inflammatory amplifier in AD, PD, and ALS models. Central-peripheral inflammatory communication and cell-specific HMGB1 release further shape these responses. Clinical studies have associated total HMGB1 or anti-HMGB1 autoantibodies with clinical features, but current assays do not resolve redox form, cellular source, or biological activity. Most therapeutic studies remain preclinical, while available human intervention studies involve drugs with multiple molecular actions. Clinical translation requires redox-resolved and standardized assays, longitudinal human sampling, compartment- and cell-specific causal studies, and interventions with documented target engagement, central nervous system exposure, and long-term safety. HMGB1 is best understood as a context-dependent mediator rather than a uniformly pathogenic factor or a single treatment target.},
}

Humans
*HMGB1 Protein/metabolism/genetics
*Neurodegenerative Diseases/metabolism
Animals
Translational Research, Biomedical
Signal Transduction
Alarmins/metabolism
Biomarkers

@article {pmid42873357,
year = {2026},
author = {Gündoğdu, AA and Özkan, NG and Adapınar, DÖ},
title = {The small giant actor in the pathogenesis of neurodegenerative diseases: Microtubules.},
journal = {Metabolic brain disease},
volume = {41},
number = {1},
pages = {},
pmid = {42873357},
issn = {1573-7365},
mesh = {Humans ; *Microtubules/metabolism/pathology ; *Neurodegenerative Diseases/metabolism/pathology ; Animals ; tau Proteins/metabolism ; Axonal Transport/physiology ; },
abstract = {Neurodegenerative diseases are a clinically and pathologically diverse group of disorders characterized by progressive neuronal dysfunction, synaptic impairment, and neuronal loss. Although research has traditionally focused on disease-associated protein misfolding and aggregation, increasing evidence implicates abnormalities of cytoskeletal organization and intracellular transport in several neurodegenerative conditions. Microtubules contribute to neuronal polarity, axonal and dendritic transport, organelle distribution, and synaptic maintenance. These functions are regulated in part by tubulin isotypes, post-translational modifications collectively described as the tubulin code, microtubule-associated proteins, and molecular motors. This narrative review examines evidence linking alterations in these processes with Alzheimer's disease, Parkinson's disease, frontotemporal dementia, Huntington's disease, amyotrophic lateral sclerosis, and prion disease. We summarize proposed interactions among microtubule instability, impaired axonal transport, mitochondrial dysfunction, and disease-associated proteins, including tau, α-synuclein, mutant huntingtin, TDP-43, and prion protein. Evidence connecting tau pathology with microtubule dysfunction is comparatively well established in Alzheimer's disease and MAPT-related tauopathies, whereas findings in other disorders are more heterogeneous and are frequently derived from cellular or animal models. We also discuss emerging experimental approaches, candidate biomarkers, and investigational microtubule-directed treatments. However, no tubulin-specific biomarker or microtubule-targeted disease-modifying treatment discussed in this review has yet been clinically validated. Overall, microtubule dysfunction may represent one component of broader, disease-specific pathological networks rather than a universal primary cause of neurodegeneration. Further longitudinal and clinical studies are needed to determine whether microtubule-related alterations act as causes, consequences, or modifiers of disease progression.},
}

Humans
*Microtubules/metabolism/pathology
*Neurodegenerative Diseases/metabolism/pathology
Animals
tau Proteins/metabolism
Axonal Transport/physiology

@article {pmid42875680,
year = {2026},
author = {Gupta, R and Kumar, R and K S, BS and Modi, DK and Kumari, S and Kumar, N and Singh, P and Ravi, K and Abomughaid, MM},
title = {Restoring Neural Homeostasis via Class II HDAC Modulation: Mechanistic Insights and Therapeutic Opportunities.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42875680},
issn = {1559-1182},
mesh = {Humans ; *Histone Deacetylases/metabolism ; Animals ; *Homeostasis/drug effects/physiology ; Neurodegenerative Diseases ; Histone Deacetylase Inhibitors/pharmacology/therapeutic use ; *Neurons/metabolism/drug effects ; Signal Transduction ; },
abstract = {Class II histone deacetylases (HDACs) comprise class IIa enzymes HDAC4, HDAC5, HDAC7, and HDAC9 and class IIb enzymes HDAC6 and HDAC10, which differ substantially in structure, catalytic activity, subcellular localization, and neural function. Class IIa HDACs exhibit weak intrinsic deacetylase activity and function predominantly as signal-responsive scaffolds that couple calcium and kinase signaling to transcription through nucleocytoplasmic shuttling, recruitment of HDAC3-containing NCoR/SMRT corepressor complexes, and interactions with MEF2, CREB, and FOXO. Conversely, HDAC6 is a predominantly cytoplasmic deacetylase that regulates α-tubulin acetylation, cytoskeletal dynamics, axonal transport, autophagy, and proteostasis. Dysregulated class II HDAC signaling contributes to neurodegenerative diseases through convergent mechanisms involving synaptic dysfunction, maladaptive transcriptional repression, mitochondrial impairment, oxidative stress, neuroinflammation, blood-brain barrier disruption, and defective clearance of pathological proteins. Disease-associated substrates include amyloid-β and tau in Alzheimer's disease, α-synuclein in Parkinson's disease, mutant huntingtin in Huntington's disease, and TDP-43/SOD1 in amyotrophic lateral sclerosis. Emerging evidence additionally links aberrant HDAC4/5 signaling to neurodevelopmental disorders through altered synaptic maturation, excitation-inhibition balance, and circuit development. This review integrates the structural and mechanistic biology of class II HDACs with their disease-specific roles and evaluates therapeutic approaches to restore neural homeostasis. Particular emphasis is placed on selective HDAC6 inhibitors, modulation of class IIa protein-protein interactions and subcellular trafficking, natural compounds, and RNA-based strategies. Finally, we discuss major translational challenges, including isoform specificity, brain penetration, context-dependent functions, and the need to distinguish catalytic from non-enzymic mechanisms when developing disease-modifying interventions for neurological disorders while preserving normal essential HDAC functions and minimizing off-target toxicity.},
}

Humans
*Histone Deacetylases/metabolism
Animals
*Homeostasis/drug effects/physiology
Neurodegenerative Diseases
Histone Deacetylase Inhibitors/pharmacology/therapeutic use
*Neurons/metabolism/drug effects
Signal Transduction

@article {pmid42875960,
year = {2026},
author = {Zhang, W and Sun, Y and Liao, ZY and Xue, B and Ju, SY and Wan, YJ and Wang, YJ},
title = {Recent Advances in Engineering Ammonia Lyase for Biosynthesis of Aromatic Noncanonical Amino Acids.},
journal = {Biotechnology journal},
volume = {21},
number = {10},
pages = {e70321},
doi = {10.1002/biot.70321},
pmid = {42875960},
issn = {1860-7314},
support = {LQN26B060007//Zhejiang Provincial Natural Science Foundation of China/ ; 2025C01097//"Pioneer" and "Leading Goose" Key R&D Program of Zhejiang/ ; 22178318//National Natural Science Foundation of China/ ; 22608515//National Natural Science Foundation of China/ ; 2025M771186//China Postdoctoral Science Foundation/ ; },
mesh = {*Ammonia-Lyases/metabolism/genetics/chemistry ; *Protein Engineering/methods ; *Amino Acids, Aromatic/biosynthesis/chemistry/metabolism ; Biocatalysis ; },
abstract = {Aromatic noncanonical amino acids (aromatic ncAAs) are valuable building blocks for pharmaceuticals, agrochemicals, food additives, and specialty chemicals, yet their sustainable and stereoselective synthesis remains challenging. Ammonia-lyases (ALs) have emerged as powerful biocatalysts for the one-step asymmetric hydroamination of arylacrylic acids, and recent advances in protein engineering have substantially enhanced their catalytic performance including efficiency, selectivity, promiscuity, and productivity. This review integrates catalytic mechanisms with the deployment of engineering strategies to illustrate how aromatic amino acid ammonia-lyases (AALs) have evolved into versatile biocatalysts for aromatic ncAAs synthesis. Particular attention is devoted to the engineering of AALs (including phenylalanine, tyrosine, histidine ammonia lyase) and (methyl)aspartate ammonia lyases, highlighting progress in substrate scope expansion, catalytic promiscuity, selectivity modulation, and hybrid catalytic systems. Current limitations and emerging opportunities are further assessed to delineate future directions for next-generation ALs engineering. The engineering strategies and current states of ALs summarized herein provide a conceptual basis for the efficient development of ALs for sustainable aromatic ncAAs biomanufacturing.},
}

*Ammonia-Lyases/metabolism/genetics/chemistry
*Protein Engineering/methods
*Amino Acids, Aromatic/biosynthesis/chemistry/metabolism
Biocatalysis

@article {pmid42878739,
year = {2026},
author = {Sanghai, N and Tranmer, GK},
title = {Diagnostic evolution of carbonic anhydrase 3 (CA3) in Amyotrophic Lateral Sclerosis (ALS): an emerging prognostic biomarker.},
journal = {Expert review of neurotherapeutics},
volume = {},
number = {},
pages = {1-7},
doi = {10.1080/14737175.2026.2748281},
pmid = {42878739},
issn = {1744-8360},
abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease traditionally viewed as a motor neuron disorder in which muscle atrophy occurs secondary to neuronal loss. However, recent clinical proteomic advances have highlighted carbonic anhydrase 3 (CA3), a muscle-enriched enzyme, as a promising biomarker associated with ALS disease progression. Therefore, considering ALS a neurocentric disease is not untenable.

AREAS COVERED: In this review, the authors examined the emergence of CA3 as an ALS biomarker and evaluated evidence from recent large-scale clinical consortium studies supporting its diagnostic and prognostic utility. They also compare CA3 with established biomarkers, neurofilament light chain (NEFL), a surrogate endpoint approved by the FDA.

EXPERT OPINION: Discoveries of CA3 biomarker in ALS highlight that peripheral skeletal muscle is not merely a passive bystander, but an integral participant in ALS disease progression. Unlike NEFL, which primarily reflects neuroaxonal injury, CA3 may capture early neuromuscular dysfunction preceding motor neuron degeneration. CA3's emergence as an ALS biomarker supports a more integrated neuromuscular model of ALS and provides a compelling rationale for incorporating CA3 into multimodal diagnostic, prognostic, and pharmacodynamic biomarker panels to accelerate ALS drug discovery, therapeutic evaluation, and precision clinical trial development, highlighting their complementary roles in early diagnosis, patient stratification, and therapeutic clinical trial design.},
}

@article {pmid42880056,
year = {2026},
author = {Wang, M and Li, J and Wang, X and Chai, X and Luo, J and Zhang, Y and Chang, X and Sun, Y and Wang, H},
title = {Harnessing cGAS-STING in neurodegeneration: From mitochondrial DNA leakage and microglial reactivity to species-specific translational barriers.},
journal = {Cytokine & growth factor reviews},
volume = {92},
number = {},
pages = {101537},
doi = {10.1016/j.cytogfr.2026.101537},
pmid = {42880056},
issn = {1879-0305},
abstract = {The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, a cornerstone of innate immunity, has emerged as a critical driver of sterile neuroinflammation in the aging brain. Age-related decline in mitochondrial quality control, coupled with nuclear and lysosomal erosion, fosters the aberrant accumulation of cytosolic self-DNA, establishing a permissive environment for chronic cGAS-STING activation. This review synthesizes recent breakthroughs elucidating how major neurodegenerative diseases-Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease-converge on this pathway through distinct, disease-specific triggers, ranging from PINK1/Parkin deficiency-driven mitochondrial DNA leakage to TDP-43 proteinopathy-associated retrotransposon de-repression. Critically, we evaluate the translational landscape, highlighting the profound challenge posed by species-specific pharmacology, as exemplified by the failure of the covalent inhibitor H-151 to engage human STING. We argue that the future of therapeutic intervention lies not in wholesale pathway ablation, but in nuanced, context-dependent fine-tuning that disentangles its detrimental chronic effects from its indispensable homeostatic functions. This review positions the cGAS-STING axis as a promising yet delicate frontier for combating age-related neurodegeneration.},
}

@article {pmid42880226,
year = {2026},
author = {DeAngelo, JD and Silverstein, AM and Shechter, D},
title = {Protein arginine methylation rewires molecular interactions.},
journal = {Cell chemical biology},
volume = {33},
number = {10},
pages = {1404-1421},
doi = {10.1016/j.chembiol.2026.09.011},
pmid = {42880226},
issn = {2451-9448},
mesh = {*Arginine/metabolism/chemistry ; Methylation ; *Protein-Arginine N-Methyltransferases/metabolism/chemistry ; Humans ; Protein Binding ; *Intrinsically Disordered Proteins/metabolism/chemistry ; },
abstract = {Protein arginine methyltransferases (PRMT1-9) catalyze monomethylation and dimethylation of arginine residues in RNA- and DNA-associated proteins. Protein arginine methylation can weaken or strengthen nucleic acid binding, recruit or exclude protein partners, and promote or suppress higher-order assembly, making its molecular consequences highly context dependent. Methylation preserves the cationic character of the guanidinium group, while altering hydrogen-bond donor topology, steric accessibility, and interaction geometry. These effects are particularly consequential in intrinsically disordered regions (IDRs), where arginine-rich motifs mediate multivalent protein-protein and protein-nucleic acid interactions. Here, we propose an interaction-equilibrium framework in which arginine methylation redistributes binding capacity among the competing protein, nucleic acid, and assembly states. This framework integrates reader-dependent and reader-independent effects of methylarginine and provides a chemical basis for understanding how a charge-preserving modification can reweight molecular interactions across diverse cellular contexts.},
}

*Arginine/metabolism/chemistry
Methylation
*Protein-Arginine N-Methyltransferases/metabolism/chemistry
Humans
Protein Binding
*Intrinsically Disordered Proteins/metabolism/chemistry

@article {pmid42865955,
year = {2026},
author = {Long, Z and Guo, H and Sun, L},
title = {Mesenchymal stromal cells in age-related neurodegenerative disorders: mechanisms, translational barriers, and precision strategies.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1965598},
pmid = {42865955},
issn = {1664-3224},
mesh = {Humans ; *Neurodegenerative Diseases/therapy/metabolism/etiology ; *Mesenchymal Stem Cells/metabolism/immunology ; Animals ; *Aging/immunology ; Extracellular Vesicles/metabolism/transplantation ; *Mesenchymal Stem Cell Transplantation/methods ; Precision Medicine ; Translational Research, Biomedical ; },
abstract = {Ageing remodels the neuroimmune, metabolic, and vascular environment in ways that accelerate neuronal vulnerability and constrain tissue repair. Mesenchymal stromal cells (MSCs) and MSC-derived extracellular vesicles (MSC-EVs) are therefore attractive candidates for neurodegenerative disorders because their effects extend beyond cell replacement to coordinated paracrine, immunomodulatory, trophic, and vascular regulation. This critical review evaluates the biological rationale, disease-specific evidence, translational limitations, and precision-development strategies for MSC-based interventions in Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple system atrophy, and vascular dementia, whilst using selected rare hereditary neurodegenerative disorders as exploratory boundary cases. Current evidence supports three interconnected modes of action: reprogramming maladaptive neuroimmune responses; preserving neuronal homeostasis through trophic support, mitochondrial rescue, and proteostasis regulation; and restoring the neurovascular unit and blood-brain barrier. However, reproducible clinical efficacy remains limited by variation in tissue source, donor age, manufacturing, potency, dose, route, and outcome selection, as well as poor central nervous system exposure and inadequate patient stratification. Ageing-related changes in both the recipient microenvironment and the cellular product further complicate translation. Future development should replace empirical cell administration with mechanism-defined products, validated potency assays, quantitative biodistribution, biomarker-guided enrolment, engineered cells or vesicles, rational combinations, and trials using disease-modifying endpoints. MSC-based therapies are best positioned not as universal regenerative agents, but as mechanism-defined, biomarker-matched products-potentially engineered at the cell or EV level-that regulate biologically active and potentially reversible disease states.},
}

Humans
*Neurodegenerative Diseases/therapy/metabolism/etiology
*Mesenchymal Stem Cells/metabolism/immunology
Animals
*Aging/immunology
Extracellular Vesicles/metabolism/transplantation
*Mesenchymal Stem Cell Transplantation/methods
Precision Medicine
Translational Research, Biomedical

@article {pmid42869255,
year = {2026},
author = {Zhang, ZY and Qin, BQ and Wu, SZ and Zhang, H},
title = {Conformational allocation of mitofusin 2 in neuronal mitochondrial dynamics: Mechanisms and therapeutic targeting.},
journal = {Biochemical pharmacology},
volume = {},
number = {},
pages = {118545},
doi = {10.1016/j.bcp.2026.118545},
pmid = {42869255},
issn = {1873-2968},
abstract = {Neurons must sustain functional mitochondria far from the cell body. Mitofusin 2 (MFN2), a dynamin-like large guanosine triphosphatase (GTPase), coordinates outer mitochondrial membrane remodeling with axonal transport, bioenergetic support, inter-organelle communication, and stress-responsive quality control. Studying these activities separately obscures how disruption of one protein produces diverse neuronal phenotypes. We propose a testable conformational-allocation framework in which molecular state distributions and transition kinetics bias MFN2 participation across cellular outputs. Integrating structural and functional evidence, we distinguish experimentally resolved mechanisms from working models. Variants associated with Charcot-Marie-Tooth disease type 2A (CMT2A) are compared by the molecular step or functional output affected. Fusion loss alone does not capture this mechanistic diversity. Structure-guided docking supports local compatibility at a shallow, conformationally conditional C-terminal surface, without establishing native accessibility, affinity, or therapeutic response. CMT2A provides the strongest context for intervention, combining causal genetics, direct mitofusin engagement studies, and multiscale rescue. Amyotrophic lateral sclerosis (ALS) provides secondary preclinical evidence, whereas Alzheimer's and Parkinson's diseases remain exploratory. The mitofusin pathway is chemically tractable, but paralog selectivity and state-dependent target engagement remain unresolved. A state- and variant-informed strategy may better match intervention to the affected output than indiscriminate enhancement of fusion.},
}

@article {pmid42869990,
year = {2026},
author = {Castro, J and de Carvalho, M and Swash, M},
title = {Revisiting the muscle spindle in ALS: Implications for spinal motor network dysfunction.},
journal = {Pflugers Archiv : European journal of physiology},
volume = {478},
number = {11},
pages = {},
pmid = {42869990},
issn = {1432-2013},
mesh = {*Amyotrophic Lateral Sclerosis/physiopathology/pathology ; Humans ; Animals ; *Muscle Spindles/physiopathology/physiology ; *Motor Neurons/physiology ; Motor Neurons, Gamma/physiology ; *Spinal Cord/physiopathology ; Interneurons/physiology ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is typically characterized by progressive degeneration of upper and lower motor neurons. However, the contribution of afferent sensory pathways to spinal motor network disorganization has received little attention. Converging human histological evidence from multiple independent laboratories demonstrates that fusimotor (gamma) motor neuron innervation of muscle spindles degenerates in ALS while sensory endings remain morphologically intact at the end organ, although the afferent neurons and ascending sensory pathways are also affected. This dissociation creates unmodulated proprioceptive input. Spindle-derived sensory signals reach spinal interneuron circuits without fusimotor gain-control adjustment, degrading spindles from forward sensory models encoding predicted kinematic states into crude stretch receptors. We propose that this gain-control failure, compounded by the loss of associated alpha-gamma coactivation and beta skeletofusimotor denervation, constitutes an upstream driver of the spinal inhibitory interneuron circuit dysfunction documented by recent electrophysiological studies in ALS. The resulting early disinhibition, followed by maladaptive excitation, mirrors cortical ALS pathophysiology. However, transgenic mouse ALS models show selective sparing of gamma motor neurons, unlike the human disease, constituting a critical translational limitation. We present a temporal model of human ALS, linking fusimotor denervation to progressive disruption of spinal inhibitory and excitatory circuits.},
}

*Amyotrophic Lateral Sclerosis/physiopathology/pathology
Humans
Animals
*Muscle Spindles/physiopathology/physiology
*Motor Neurons/physiology
Motor Neurons, Gamma/physiology
*Spinal Cord/physiopathology
Interneurons/physiology

@article {pmid42862306,
year = {2026},
author = {Sahu, S and Jain, P and Dharme, KK and Yadav, K},
title = {CRISPR/Cas9-based nanodelivery systems for precision gene editing in neuroinflammation.},
journal = {Inflammation research : official journal of the European Histamine Research Society ... [et al.]},
volume = {75},
number = {1},
pages = {},
pmid = {42862306},
issn = {1420-908X},
support = {Probecell/Res/2026/124//Probecell Scientific Pvt. Ltd./ ; },
mesh = {Humans ; Animals ; *Neuroinflammatory Diseases/genetics/therapy ; *Gene Editing/methods ; *CRISPR-Cas Systems ; Nanoparticles/administration & dosage ; },
abstract = {BACKGROUND: Neuroinflammation is a characteristic feature of many neurological diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Uncontrolled activation of microglia and astrocytes results in the production of proinflammatory mediators that contribute to neuronal dysfunction and degeneration.

PURPOSE: CRISPR/Cas9 genome-editing technology provides highly precise targeting of genes involved in these pathways, enabling the deletion, correction, or modulation of disease-associated genetic alterations. Nonetheless, effective delivery of CRISPR components to the central nervous system (CNS) remains a major challenge because of protective barriers such as the blood-brain barrier (BBB), as well as concerns regarding genomic instability and immunogenicity.

METHODS: Nanotechnology-guided delivery platforms, such as lipid nanoparticles, liposomes, dendrimers and polymeric carriers, have been developed as promising strategies to address these challenges. These nanosystems can improve biodistribution, pharmacokinetic behavior, and cellular uptake, while potentially reducing off-target effects and systemic toxicity.

RESULTS: The preclinical studies demonstrate successful modulation of key neuroinflammatory targets, including the NLRP3 inflammasome, triggering receptor expressed on myeloid cells 2 (TREM2), Janus kinase (JAK) signaling, and the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway, with potential therapeutic relevance to neurodegenerative diseases. In addition, novel techniques, such as mitochondrial base editing, prime editing, and epigenetic modulation, expand the scope of CRISPR-mediated therapeutic strategies. Although outcomes from animal models are promising, translation to the clinical setting requires careful consideration of safety, ethical concerns, and long-term efficacy.

CONCLUSIONS: This review highlights the potential of integrating CRISPR/Cas9 with nanodelivery systems to advance precision medicine for neuroinflammatory disorders, while emphasizing their potential for therapeutic applications in complex CNS conditions. Ongoing studies aimed at optimizing delivery and reducing off-target effects will be essential for advancing these approaches toward clinical practice.},
}

Humans
Animals
*Neuroinflammatory Diseases/genetics/therapy
*Gene Editing/methods
*CRISPR-Cas Systems
Nanoparticles/administration & dosage

@article {pmid42862794,
year = {2026},
author = {Hawas, Y and Abdelmageed, A and Messak, M and Ziada, A and Gamal, M and Ghanem, TIE and Abdelwahab, MM and Meshref, M and Kashbour, MO},
title = {History of Head Injury and Risk of Amyotrophic Lateral Sclerosis: An Updated Comprehensive Systematic Review with Meta-Analysis of 5,033,215 Participants.},
journal = {Neuroepidemiology},
volume = {},
number = {},
pages = {1},
doi = {10.1159/ned/adwag050},
pmid = {42862794},
issn = {1423-0208},
abstract = {BACKGROUND: Head injury has been proposed as a potential modifiable risk factor for amyotrophic lateral sclerosis (ALS); however, prior studies have yielded inconsistent findings. We aimed to re-evaluate this association through an updated systematic review and meta-analysis, incorporating the latest evidence and exploring the influence of injury severity, frequency, timing, and definition.

METHODS: A systematic search of PubMed, Scopus, Web of Science, Embase, EBSCO, and ProQuest from inception to January 2026 was conducted. Observational studies (cohort and case-control) reporting the association between head injury and ALS risk were included. Pooled effect estimates were generated using random-effects models. Subgroup, sensitivity, cumulative, and publication bias analyses were performed.

RESULTS: Twenty-nine studies encompassing 5,033,215 participants were included. These comprised 22 case-control studies and seven cohort studies. Case-control meta-analysis showed that head injury was associated with 36% higher odds of ALS (AOR = 1.36; 95% CI: 1.24-1.48; I² = 20.4%). Cohort studies showed a positive but non-significant association (RR = 1.59; 95% CI: 0.93-2.71). Subgroup analyses showed significant associations within mild, moderate, and severe injury categories and among studies with clearly defined traumatic brain injury exposure. Single head injury was associated with higher odds of ALS (AOR = 1.22; 95% CI: 1.11-1.34).

CONCLUSION: Head injury was associated with an increased risk of ALS across multiple analyses, including different injury severity levels and exposure definitions. However, the observational nature of available evidence and the possibility of reverse causation and residual confounding limit causal interpretation. Further prospective studies and mechanistic investigations are required to clarify the potential relationship between head injury and ALS development.},
}

@article {pmid42864786,
year = {2026},
author = {Hokkoku, K},
title = {[Lumbar Spinal Disease or Peripheral Nerve Disorder? The Role of Neurological Examination in Differential Diagnosis].},
journal = {Brain and nerve = Shinkei kenkyu no shinpo},
volume = {78},
number = {10},
pages = {1089-1096},
doi = {10.11477/mf.188160960780101089},
pmid = {42864786},
issn = {1881-6096},
mesh = {Humans ; Diagnosis, Differential ; *Peripheral Nervous System Diseases/diagnosis ; *Neurologic Examination ; Nerve Conduction Studies ; *Spinal Diseases/diagnosis ; },
abstract = {Lower-limb numbness, pain, and weakness are common clinical complaints that require differentiation between cauda equina or radicular lesions associated with lumbar spinal disease and peripheral nerve disorders. Because degenerative findings on lumbar imaging are common, particularly among older adults, the responsible lesion should not be determined based on imaging findings alone. In this context, neurological examination contributes to anatomical localization and is central to the differential diagnosis. Particular emphasis is placed on interpreting muscle weakness and sensory disturbance according to myotomal, dermatomal, and peripheral nerve distributions. Other neurological findings, including gait disturbance, neurogenic claudication, bladder or bowel dysfunction, nerve stretch signs, and reflex changes, also provide important clues for localization. This review further addresses common diagnostic challenges encountered in daily practice, including differentiation of L5 radiculopathy from fibular neuropathy in patients with foot drop, distinction between cauda equina lesions and polyneuropathy, recognition of immune-mediated polyradiculoneuropathies, and identification of amyotrophic lateral sclerosis when it mimics lumbar spinal disease. Ancillary tests such as nerve conduction studies, needle electromyography, somatosensory evoked potentials, nerve ultrasound, and imaging should be interpreted in relation to the lesion localization suggested by neurological examination.},
}

Humans
Diagnosis, Differential
*Peripheral Nervous System Diseases/diagnosis
*Neurologic Examination
Nerve Conduction Studies
*Spinal Diseases/diagnosis

@article {pmid42865281,
year = {2026},
author = {Pini, A and Cobel, C and Moretti, F and Governatori, G and Bonamici, M and Gobbato, T and Buonaccorso, L and Sireci, F and Ghirotto, L},
title = {Mapping the evidence on dignity therapy in amyotrophic lateral sclerosis: a scoping review.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-10},
doi = {10.1080/21678421.2026.2742818},
pmid = {42865281},
issn = {2167-9223},
abstract = {Objective: To systematically map and synthesize the existing literature on the use of Dignity Therapy (DT) in amyotrophic lateral sclerosis (ALS), with particular attention to feasibility, acceptability, therapeutic outcomes, and clinical adaptations required for patients and caregivers. Methods: A systematic scoping review was conducted searching PubMed/MEDLINE, CINAHL, PsycINFO, and Scopus for studies published in the last ten years examining DT in individuals with ALS. Eligible studies were charted and compared qualitatively due to heterogeneity in design, outcomes, and measurement tools. Results: A total of 237 records were identified, of which five met the eligibility criteria. DT was generally feasible in ALS, including in advanced disease stages, when adapted with augmentative communication devices, email correspondence, or videoconferencing. Acceptability was high across studies, with participants frequently reporting meaningful engagement with the narrative process and positive perceptions of the generativity document. Qualitative evidence indicated potential benefits in existential well-being, emotional adjustment, maintenance of identity, and family communication. Quantitative outcomes were inconsistent, showing variable effects on dignity-related distress, mood symptoms, and spiritual well-being. Caregiver responses were mixed, with some reporting perceived support and others noting limited immediate impact. Conclusions: DT appears to be a promising intervention for addressing existential and relational needs in ALS, though current evidence is limited by small sample sizes and methodological variability. Larger, methodologically rigorous studies are needed to clarify therapeutic effects, optimize delivery adaptations, and evaluate outcomes for both patients and caregivers.},
}

@article {pmid42636000,
year = {2026},
author = {Benatar, M and Barmada, S and Jicha, GA and Lagier-Tourenne, C and Gregory, J and Al-Chalabi, A and Boeve, BF and Jack, CR and Seeley, WW and Maragakis, NJ and Wuu, J and Zeier, Z and Onyike, C and Lewcock, J and Hovinga, C and Jafar-Nejad, P and Uspenskaya, O and Simmons, A and Browne, SE and Rohrer, J and Petrucelli, L and Shapiro, J and Scharper, D and Boxer, A and Ostrow, LW and Staffaroni, AM and Dacks, P and Turner, MR and Dave, KD and de Majo, M and Mitic, L and Fradette, S and Budd Haeberlein, S and Simuni, T and Dunn, B and McMillan, CT and Lee, EB},
title = {TDP-43-Associated Neurodegenerative Disease Conceptualization and Integrated Staging: A Review.},
journal = {JAMA neurology},
volume = {83},
number = {10},
pages = {1013-1022},
doi = {10.1001/jamaneurol.2026.2812},
pmid = {42636000},
issn = {2168-6157},
mesh = {Humans ; *Neurodegenerative Diseases/classification/pathology/genetics/metabolism/diagnosis ; *DNA-Binding Proteins/metabolism/genetics ; Biomarkers/metabolism ; *TDP-43 Proteinopathies/classification/pathology ; },
abstract = {IMPORTANCE: Classifying disease based on underlying pathobiology rather than clinical phenotype has implications for the development of biomarkers and therapy development.

OBSERVATIONS: Transactive response DNA-binding protein 43 kDa (TDP-43) pathology is observed across a range of clinically defined neurodegenerative disorders including limbic predominant age-related encephalopathy (LATE), most cases of amyotrophic lateral sclerosis (ALS), inclusion body myositis, multisystem proteinopathy, and approximately half the cases of frontotemporal dementia (FTD). Despite this shared biology, the current nosology for these neurodegenerative disorders is based on their distinct clinical phenotypes. An alternative approach recognizes the central role of TDP-43 pathology in disease pathogenesis, reserving the use of clinical terms like ALS, FTD, or LATE to describe phenotypic manifestations of underlying pathobiology. This approach also recognizes the converging biomarker and neuropathological data indicating that pathology begins presymptomatically, before the overt clinical manifestations of disease appear.

CONCLUSIONS AND RELEVANCE: In proposing a pathobiological definition of disease, the goal is to provide a road map for developing biomarkers that accurately reflect the underlying pathobiology of disease and for advancing therapeutic candidates that effectively target fundamental disease mechanisms.},
}

Humans
*Neurodegenerative Diseases/classification/pathology/genetics/metabolism/diagnosis
*DNA-Binding Proteins/metabolism/genetics
Biomarkers/metabolism
*TDP-43 Proteinopathies/classification/pathology

@article {pmid42858164,
year = {2026},
author = {Vocelle, A and Ensrud, E and Howard, IM},
title = {Prognostication in Amyotrophic Lateral Sclerosis: A Narrative Review of Pre-Diagnosis and Functional Outcomes.},
journal = {NeuroRehabilitation},
volume = {},
number = {},
pages = {10538135261490936},
doi = {10.1177/10538135261490936},
pmid = {42858164},
issn = {1878-6448},
abstract = {Amyotrophic Lateral Sclerosis (ALS) is a very heterogeneous disease, yet some of the most common questions received by physicians in the ALS clinic are "how much time do I have?" and "what can I expect to happen next?" This line of inquiry is not strictly limited to patients; clinicians also need an idea of prognosis to appropriately plan for treatment decisions and prepare the patient and caregiver for future care needs. This narrative review synthesizes current evidence on prognostic indicators in ALS, organized across three temporal phases: factors preceding diagnosis, factors present at diagnosis, and factors emerging after diagnosis. Pre-diagnosis predictors include age at onset, sex, socioeconomic status, genetic background, premorbid Body Mass Index (BMI) and nutritional status, and comorbid disease. At diagnosis, clinical phenotype and site of onset, diagnostic delay, baseline Amyotrophic Lateral Sclerosis Functional Rating Score-Revised (ALSFRS-R) and forced vital capacity, cognitive involvement, fluid biomarkers, and electrophysiologic measures carry prognostic weight. Post-diagnosis, the trajectory is refined by the rate of ALSFRS-R decline, serial respiratory measures, and weight loss, and is actively modified by clinical interventions including noninvasive ventilation, enteral nutrition, disease-modifying therapy, and multidisciplinary care. Notably, quality of life does not track with physical decline, consistent with the disability paradox described in other severe neurological conditions. For neurorehabilitation, these indicators support a shift from reactive to anticipatory practice: timing equipment provision, communication support, respiratory intervention, and goals-of-care discussions to the predicted trajectory rather than to established deficit. Refinement of prognostic models may also improve stratification in ALS clinical trials.},
}

@article {pmid42859482,
year = {2026},
author = {Sharma, T and Krishna, H and Dixit, A and Dixit, SG and Shukla, KK and Banerjee, M and Nayak, P},
title = {Aluminium as a Metalloestrogen: Toxicological Pathways, Endocrine Disruption and Systemic Health Implications.},
journal = {Maedica},
volume = {21},
number = {3},
pages = {759-766},
pmid = {42859482},
issn = {1841-9038},
abstract = {Aluminium (Al) is the most abundant metal in the Earth's crust and a common environmental contaminant due to industrial processes, recycling and consumer goods. Aluminium can enter the human body via the gastrointestinal, respiratory, and skin routes, as well as through injection, although this is not essential for biological function. It can then accumulate in different organs. Its physicochemical properties enable it to displace vital metals, bind to biomolecules and interfere with cellular processes, leading to genotoxicity, oxidative stress and protein misfolding. Aluminium toxicity impacts various body systems, such as neurodegeneration, bone disorders, heart conditions, endocrine disruption and reproductive issues. Notably, Al acts as a metalloestrogen, mimicking or disrupting estrogen receptor signaling. This interference affects the hypothalamic-pituitary-gonadal axis and changes estrogen-dependent processes in both males and females. This review explores Al's systemic toxicology and its emerging function as an endocrine disruptor, highlighting its dual nature as both a sustainable industrial resource and a common biological toxin. The findings highlight important public health issues and suggest the need for further research into how Al interacts with estrogen receptors to improve prevention and treatment.},
}

@article {pmid42862029,
year = {2026},
author = {Santos Silva, C and de Carvalho, M},
title = {Transcutaneous Carbon Dioxide Monitoring in Amyotrophic Lateral Sclerosis: A Scoping Review.},
journal = {European journal of neurology},
volume = {33},
number = {10},
pages = {e70782},
doi = {10.1111/ene.70782},
pmid = {42862029},
issn = {1468-1331},
mesh = {*Amyotrophic Lateral Sclerosis/complications/diagnosis ; Humans ; *Carbon Dioxide ; *Blood Gas Monitoring, Transcutaneous/methods ; *Hypoventilation/diagnosis/etiology ; *Respiratory Insufficiency/diagnosis/etiology ; },
abstract = {BACKGROUND: Respiratory failure is the leading cause of death in amyotrophic lateral sclerosis (ALS). Conventional pulmonary function tests are effort-dependent and may fail to detect early nocturnal hypoventilation. Transcutaneous carbon dioxide (PtcCO2) measurement is a non-invasive method for assessing ventilation, but its role in ALS remains unclear. We performed a scoping review to map the current evidence.

METHODS: PubMed, Web of Science, Scopus, and Google Scholar were searched from inception to April 2026. Original studies evaluating PtcCO2 monitoring in ALS were included. Due to heterogeneity in study designs, populations, and outcomes, a narrative synthesis was performed, categorized by study characteristics, measurement protocols, and clinical endpoints.

RESULTS: Twenty-one studies were included. Most were observational and conducted in tertiary centres. Twelve studies evaluated PtcCO2 as a surrogate marker for nocturnal hypoventilation, mainly to guide initiation or titration of non-invasive ventilation. Definitions of hypoventilation and reported PtcCO2 metrics varied widely. Only three studies evaluated PtcCO2 in relation to respiratory impairment or hypercapnia, but none reported formal measures of diagnostic accuracy. Evidence regarding the prognostic value was limited and inconsistent. Three studies showed that nocturnal hypercapnia preceded abnormalities in spirometry or daytime hypercapnia.

CONCLUSIONS: PtcCO2 monitoring shows promise as a non-invasive method for assessing nocturnal ventilatory abnormalities in ALS, including nocturnal hypoventilation. However, due to methodological heterogeneity, its diagnostic and prognostic roles remain uncertain. Current evidence is insufficient to support PtcCO2 as a standalone criterion for NIV initiation. Large-scale prospective studies with standardized protocols are essential to delineate its clinical utility.},
}

*Amyotrophic Lateral Sclerosis/complications/diagnosis
Humans
*Carbon Dioxide
*Blood Gas Monitoring, Transcutaneous/methods
*Hypoventilation/diagnosis/etiology
*Respiratory Insufficiency/diagnosis/etiology

@article {pmid42862052,
year = {2026},
author = {Unnikrishnan, B and Anand, A and Fang, CN and Wu, SM and Wang, CC and Huang, CC and Chu, HW and Chang, HT},
title = {Carbon dot-based nanomaterials in neurodegeneration: addressing neurobiological barriers and targeting challenges.},
journal = {Chemical communications (Cambridge, England)},
volume = {},
number = {},
pages = {},
doi = {10.1039/d6cc03262a},
pmid = {42862052},
issn = {1364-548X},
abstract = {Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis, represent a major global health challenge due to their progressive nature and limited therapeutic options. One of the primary obstacles to treating these disorders is the blood-brain barrier (BBB), which restricts the delivery of most therapeutic agents into the central nervous system. In recent years, carbon-based nanomaterials, particularly carbon dot (CD) nanostructures, have emerged as promising platforms for neurological applications owing to their ultrasmall size, BBB-crossing ability, and anti-inflammatory and neuroprotective properties, in addition to tunable surface chemistry, strong photoluminescence, and favorable biocompatibility. This review provides a comprehensive overview of recent research developments in the application of CD-based nanomaterials, including carbon nanodots, carbon quantum dots, graphene quantum dots, and carbon polymer dots, for the potential treatment of neurodegenerative diseases. The synthesis strategies and carbonization approaches used to produce these carbon nanomaterials are discussed, along with their physicochemical properties relevant to neurobiological applications, such as particle size, surface functionalization, heteroatom doping, optical properties, and stability in biological environments. Furthermore, the mechanisms by which CD-based nanomaterials can traverse the BBB are examined, including receptor-mediated and adsorptive-mediated transcytosis pathways. In addition, their applications are discussed, with particular focus on their roles in bioimaging, biosensing, inhibition of pathological protein aggregation, antioxidative activity, and targeted drug delivery. Finally, key challenges related to toxicity, biodistribution, large-scale synthesis, and clinical translation are discussed, along with future perspectives for the development of multifunctional theranostic platforms. Overall, use of CD-based nanomaterials represents a promising emerging strategy for overcoming neurobiological barriers and enabling the development of next-generation nanotherapeutics for the management of neurodegenerative diseases.},
}

@article {pmid42855762,
year = {2026},
author = {Wang, HF and Sun, B and Pan, J and Pang, XY and Bai, JM and Feng, JL},
title = {[The role of the GSTP1/JNK signaling pathway in regulating oxidative stress and programmed cell death in amyotrophic lateral sclerosis].},
journal = {Zhonghua nei ke za zhi},
volume = {65},
number = {10},
pages = {1122-1129},
doi = {10.3760/cma.j.cn112138-20260501-00268},
pmid = {42855762},
issn = {0578-1426},
mesh = {*Amyotrophic Lateral Sclerosis/metabolism/pathology ; *Oxidative Stress ; *Glutathione S-Transferase pi/metabolism ; Humans ; *Apoptosis ; Animals ; *MAP Kinase Signaling System ; Signal Transduction ; JNK Mitogen-Activated Protein Kinases/metabolism ; },
}

*Amyotrophic Lateral Sclerosis/metabolism/pathology
*Oxidative Stress
*Glutathione S-Transferase pi/metabolism
Humans
*Apoptosis
Animals
*MAP Kinase Signaling System
Signal Transduction
JNK Mitogen-Activated Protein Kinases/metabolism

@article {pmid42855802,
year = {2026},
author = {Zheng, X and Yu, X},
title = {A Comprehensive Review and Future Prospects of Aluminum-Sulfur Batteries: From Material Design to Practical Challenges.},
journal = {Advanced materials (Deerfield Beach, Fla.)},
volume = {},
number = {},
pages = {e06181},
doi = {10.1002/adma.202506181},
pmid = {42855802},
issn = {1521-4095},
support = {2019-01 07-00-07-E00028//Innovation Program of the Shanghai Municipal Education Commission/ ; 51971065//National Science Foundation of China/ ; },
abstract = {Aluminum-sulfur (Al-S) batteries are promising next-generation energy storage systems owing to the high abundance, low cost, and multi-electron redox capability of Al, combined with the high theoretical capacity and environmental friendliness of S. This review systematically compares the dual electrochemical mechanisms based on S reduction (S[0]/S[2-]) and S oxidation (S[0]/S[4+]), highlighting their distinct advantages in energy density and safety. Key strategies for cathode design-including carbon-based, anchoring-functional, and catalytic-functional hosts-are discussed, alongside electrolyte engineering using ionic liquids, deep eutectic solvents, inorganic molten salts, and aqueous systems. Recent advances in dendrite suppression, anode protective layers, and functional separators are also summarized. A central challenge identified is the sluggish Al[3+] solvation/desolvation kinetics, which limits rate capability and low-temperature performance. The application of in situ/operando characterization techniques (XANES, Raman, UV-vis) to unravel complex reaction pathways is emphasized. By integrating multidisciplinary innovations, this review provides a comprehensive perspective and a phased commercialization roadmap, aiming to accelerate the transition of Al-S batteries from laboratory research to practical green energy storage.},
}

@article {pmid42852066,
year = {2026},
author = {Duarte, ML and Iared, W and Oliveira, ABS and Dos Santos, LR and da Silva, MSP},
title = {Comparison between ultrasound and electromyography for detection of fasciculations in amyotrophic lateral sclerosis: an updated systematic review and meta-analysis.},
journal = {Radiologia brasileira},
volume = {59},
number = {},
pages = {e20260011},
pmid = {42852066},
issn = {0100-3984},
abstract = {Fasciculations are a key manifestation of lower motor neuron dysfunction in amyotrophic lateral sclerosis (ALS). Al-though electromyography is considered the gold-standard method for the detection of fasciculations, its sensitivity for that purpose depends on the muscle sampled and the examination time. Muscle ultrasound has emerged as a dynamic, noninvasive technique with high sensitivity for detecting spontaneous muscle activity. This updated system-atic review compares ultrasound and electromyography in terms of their performance for the detection of muscle fas-ciculations in ALS, with stratification by muscle group and observation time. A comprehensive search of the literature identified studies evaluating both techniques. Data were synthesized descriptively and, when possible, quantitatively. Ultrasound demonstrated higher or comparable detection rates across most muscle groups, particularly in muscles that are large or deep, such as the biceps brachii, tibialis anterior, and vastus lateralis. Longer ultrasound observation times, especially 60 s, were associated with substantially higher detection rates without a loss of specificity. Although electromyography is still essential for electrophysiological characterization, ultrasound offers broader muscle cover-age, excellent reproducibility, and a noninvasive approach. These findings support muscle ultrasound as a valuable complementary tool for the detection and assessment of fasciculations in patients with motor neuron disease.},
}

@article {pmid42852552,
year = {2026},
author = {Choudhury, A and Prabha, S and Saeed, MU and Sulaimani, MN and Hassan, MI},
title = {Targeting protein misfolding and aggregation in neurodegenerative diseases: challenges for the identification and validation of targets for small molecules.},
journal = {Expert opinion on therapeutic targets},
volume = {},
number = {},
pages = {},
doi = {10.1080/14728222.2026.2747518},
pmid = {42852552},
issn = {1744-7631},
abstract = {INTRODUCTION: Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and related proteinopathies are characterized by the misfolding, aggregation, and accumulation of specific proteins that disrupt neuronal homeostasis, leading to neuronal death. Despite major advances in structural biology and molecular neuroscience, identifying and validating druggable targets in neurodegenerative diseases remains challenging. Many involved proteins are intrinsically disordered, exhibit conformational heterogeneity, and form highly dynamic toxic species.

AREAS COVERED: This review summarizes the mechanisms of protein folding, misfolding, aggregation, and prion-like propagation in major neurodegenerative proteinopathies, including amyloid-beta and tau in Alzheimer's disease, alpha-synuclein in synucleinopathies, TDP-43 and FUS in ALS/FTLD, polyglutamine-expanded proteins, prion proteins, and rare hereditary amyloidosis. We also discuss major barriers to target identification and validation, including conformational flexibility, oligomer toxicity, blood-brain barrier penetration, and target engagement complexity. Finally, we highlight emerging strategies integrating structural biology, computational methods, and improved experimental models to discover small-molecule inhibitors for neurodegenerative diseases.

EXPERT OPINION: Effective therapeutic discovery will require moving beyond single-target models toward ensemble-based validation strategies. Integrating structural biology, advanced imaging, biomarkers, and computational approaches may improve the identification of druggable targets and support precision-medicine-based interventions for neurodegenerative diseases.},
}

@article {pmid42847522,
year = {2026},
author = {Donlin-Asp, PG and Clayton, EL},
title = {Synaptic Proteostasis in Health and Disease.},
journal = {Journal of neurochemistry},
volume = {170},
number = {10},
pages = {e70565},
pmid = {42847522},
issn = {1471-4159},
support = {309570/Z/24/Z/WT_/Wellcome Trust/United Kingdom ; ARUK-SRF2022A-005//Alzheimer's Research UK/ ; //CureSynGAP/ ; 571/ALZS_/Alzheimer's Society/United Kingdom ; //Simons Initiative for the Developing Brain/ ; },
mesh = {Humans ; *Proteostasis/physiology ; *Synapses/metabolism/pathology ; Animals ; *Neurodegenerative Diseases/metabolism/pathology ; Autophagy/physiology ; *Neurons/metabolism/pathology ; Proteotoxic Stress ; },
abstract = {Neurons rely on tightly coordinated mechanisms of protein synthesis and degradation to maintain cellular homeostasis, a process known as proteostasis. Given their highly polarised and compartmentalised nature, regulation of proteostasis is especially important at neuronal synapses, which are spatially distant from the soma yet require rapid on-demand adaptation of the synaptic proteome. Neurons meet their demand for synaptic proteostasis through localised mRNA transport and translation, alongside specialised pathways for protein degradation. Recent advances reveal that thousands of transcripts localise to distal neuronal compartments and that their distribution may be shaped by RNA stability, RNA dynamics, and organelle-hitchhiking transport mechanisms. In parallel, processes such as synaptic autophagy and endolysosomal trafficking are crucial for maintaining synaptic structure and neurotransmission. Disruptions in these finely balanced mechanisms are a common underlying feature of various neurological disorders, including fragile X syndrome, amyotrophic lateral sclerosis, Parkinson's disease, and Alzheimer's disease. This overview highlights key milestones and remaining questions in synaptic proteostasis, focusing on how local protein synthesis and degradation work together to preserve synaptic integrity and how their dysregulation can lead to disease.},
}

Humans
*Proteostasis/physiology
*Synapses/metabolism/pathology
Animals
*Neurodegenerative Diseases/metabolism/pathology
Autophagy/physiology
*Neurons/metabolism/pathology
Proteotoxic Stress

@article {pmid42849148,
year = {2026},
author = {Freischmidt, A and Weishaupt, JH},
title = {Update on somatic mutations in major neurodegenerative diseases: mutational signatures in neurons and mosaicism.},
journal = {Current opinion in genetics & development},
volume = {101},
number = {},
pages = {102549},
doi = {10.1016/j.gde.2026.102549},
pmid = {42849148},
issn = {1879-0380},
abstract = {Somatic mutations in major neurodegenerative diseases are poorly understood, but research over the past 2 years provides valuable insights. Single-cell whole-genome sequencing of vulnerable neurons in Alzheimer's disease and amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) revealed excess accumulation of single-nucleotide variant signatures and two-bp deletions independent of pathogenic protein aggregation. Increased oxidative DNA damage and possibly impaired DNA damage repair pathways may explain more pronounced signatures in patients. Ultra-deep sequencing of disease-associated genes in relevant tissues in ALS/FTD identified a subset of sporadic patients carrying mosaic variants that cause disease when present in the germline, but the pathogenicity of such mosaic variants at low allele frequencies is unclear. Research on somatic variants in Parkinson's disease remains underrepresented in the literature.},
}

@article {pmid42850529,
year = {2026},
author = {Reilich, P and Schöberl, F},
title = {[Amyotrophic lateral sclerosis: Specific considerations in palliative care].},
journal = {MMW Fortschritte der Medizin},
volume = {168},
number = {17},
pages = {51-54},
doi = {10.1007/s15006-026-6225-z},
pmid = {42850529},
issn = {1613-3560},
}

@article {pmid42851615,
year = {2026},
author = {Ohara, M and Ishigaki, S and Watts, JK and Yamada, K and Ikezu, T and Ikezu, S},
title = {Nucleic acid therapeutics in neurodegenerative disorders: emerging technologies and clinical landscape.},
journal = {Molecular neurodegeneration advances},
volume = {2},
number = {1},
pages = {41},
pmid = {42851615},
issn = {3059-4944},
abstract = {Neurodegenerative disorders have diverse etiologies from monogenic mechanisms such as toxic gain-of-function mutation in subsets of amyotrophic lateral sclerosis (ALS) to multifactorial cascades exemplified by Alzheimer's disease (AD), which feature proteostasis failure, neuroinflammation, mitochondrial dysfunction, or age-associated cellular stress. While small molecules can modulate downstream pathways, nucleic acid therapeutics (NATs) target defined RNA sequences to directly reduce pathogenic gene expression, correct or shift isoform usage via splice modulation, and tune disease-relevant networks, positioning them as promising therapeutic modalities for neurodegenerative disorders. Recent clinical applications of NATs in the central nervous system (CNS) have made significant progress by optimized chemistries, improved tolerability, and established intrathecal administration routes, supporting sustained target engagement in relevant neural and glial compartments. This review summarizes three major NAT platforms-antisense oligonucleotides, small interfering RNAs, and aptamers-by highlighting their mechanisms of action, design principles to enhance their biodistribution, durability, and safety, and emerging novel delivery strategies for CNS targeting. We further discuss emerging translational opportunities across ALS, AD, polyglutamine disorders, prion diseases, and synucleinopathies by integrating disease biology with therapeutic rationale, and by summarizing regulatory approvals, ongoing clinical trials, and next generation NATs in preclinical development.},
}

@article {pmid42851749,
year = {2026},
author = {Li, M and Li, R and Deng, Z and Zhang, L and Lv, S and Shi, J and Ma, H and Guan, W and Zhang, H and Li, J and Teng, J},
title = {Traditional Chinese botanical medicines and plant-derived bioactive compounds in amyotrophic lateral sclerosis: mechanistic evidence, translational challenges, and therapeutic opportunities.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1918967},
pmid = {42851749},
issn = {1663-9812},
abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease with limited therapeutic options, highlighting the need for multi-target interventions. Traditional Chinese botanical medicine (TCBM) interventions have attracted increasing attention as potential multi-target pharmacological candidates for ALS. In addition, a separate body of evidence derived from selected plant-derived bioactive compounds directly investigated in ALS-specific models provides complementary mechanistic insights into ALS-related pathways. However, the pharmacological mechanisms and translational potential of these two distinct evidence categories remain insufficiently summarized. This review systematically summarizes ALS-related pathological mechanisms and the molecular actions reported within these two distinct evidence categories, together with translational challenges and future research directions.

METHODS: A structured literature search was conducted in PubMed, Web of Science, and ScienceDirect up to May 2026. A total of 198 publications were retained, including 48 ALS-specific original intervention studies forming the core pharmacological evidence set.

RESULTS: ALS involves interconnected pathological processes, including neuroinflammation, oxidative stress, mitochondrial dysfunction, impaired proteostasis, excitotoxicity, and neuromuscular junction injury. Evidence across these two categories suggests modulation of multiple ALS-related pathological processes. Reported effects include regulation of inflammatory signaling, enhancement of Nrf2-mediated antioxidant responses, improvement of PGC-1α/MFN2-associated mitochondrial homeostasis, and promotion of protein clearance pathways.

CONCLUSION: Together, these distinct but complementary evidence categories highlight the potential for multi-target modulation of ALS-related pathology. However, current evidence remains predominantly preclinical, and clinical efficacy and translational feasibility require further validation.},
}

@article {pmid42851781,
year = {2026},
author = {Smeyers, J and Mordes, DA},
title = {Minding the gates: dual cell-autonomous and non-cell-autonomous mechanisms of TBK1 in ALS/FTD.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1941293},
pmid = {42851781},
issn = {1662-4548},
abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) comprise a neurodegenerative disease spectrum characterized by TDP-43 pathology and overlapping genetic risk factors. Loss-of-function variants in TBK1 (TANK-binding kinase 1) represent one of the most common genetic causes of ALS/FTD, highlighting haploinsufficiency for TBK1 as a major contributor to disease pathogenesis. Emerging evidence from iPSC and mouse models suggests that reduced TBK1 activity disrupts interconnected autophagy, endo-lysosomal, and innate immune pathways through both cell-autonomous and non-cell-autonomous mechanisms. In this review, we discuss the multifaceted role of TBK1 as a master regulator of proteostasis and inflammatory pathways, highlight its critical role in maintaining microglial homeostasis, and explore how these convergent functions inform therapeutic strategies for ALS/FTD.},
}

@article {pmid42842169,
year = {2026},
author = {Singh, RK and Banerjee, C and Mehan, S},
title = {Beyond Histamine Blockade: Clemastine Fumarate as a Promoter of Myelin Regeneration, Inflammatory Regulation, and Neuroimmune Modulation in CNS Disorders.},
journal = {Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology},
volume = {21},
number = {1},
pages = {},
pmid = {42842169},
issn = {1557-1904},
mesh = {Animals ; Humans ; *Clemastine/pharmacology/therapeutic use ; *Central Nervous System Diseases/drug therapy/immunology/metabolism ; *Myelin Sheath/drug effects ; *Neuroimmunomodulation/drug effects/physiology ; *Remyelination/drug effects/physiology ; Neuroinflammatory Diseases/drug therapy/immunology ; *Histamine H1 Antagonists/pharmacology/therapeutic use ; },
abstract = {Clemastine fumarate, a first-generation H1 antihistamine, has emerged as a promising candidate for drug repurposing in neurodegenerative and neuropsychiatric disorders owing to its ability to cross the blood-brain barrier and interact with multiple central nervous system targets. Experimental studies indicate that clemastine promotes remyelination by stimulating the differentiation of oligodendrocyte precursor cells into mature, myelin-producing oligodendrocytes, thereby restoring myelin integrity and improving axonal function in experimental models. In addition to its remyelinating properties, preclinical evidence suggests that clemastine may attenuate neuroinflammation by modulating microglial activation and suppressing pro-inflammatory signalling pathways. These effects have been associated with improved structural and functional outcomes in experimental models of multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, spinal cord injury, stroke, and several neuropsychiatric disorders. Mechanistically, clemastine primarily acts through muscarinic M1 receptor antagonism to promotes remyelination, while additional pathways including PI3K/Akt, ERK1/2, autophagy-related signalling, inflammasome modulation, and sigma-1 receptor signalling have been proposed based on experimental evidence but remain incompletely understood and require further mechanistic validation. Among the neurological disorders investigated multiple sclerosis currently has the strongest clinical evidence with early clinical trials demonstrating modest remyelinating activity. In contrast, evidence supporting the use of clemastine in other neurological disorders remains largely confined to preclinical studies. Several translational challenges also remain unresolved including dose optimisation, treatment timing, long-term safety, sedative and anticholinergic adverse effects, and patient selection. Future research should focus on refining pharmacokinetic properties, optimising dosing strategies, evaluating rational combination therapies, and identifying predictive biomarkers to facilitate clinical translation. Although current evidence highlights the therapeutic potential of clemastine fumarate, its application beyond multiple sclerosis remains investigational and will require rigorous mechanistic studies together with well-designed clinical trials before broader clinical use can be established.},
}

Animals
Humans
*Clemastine/pharmacology/therapeutic use
*Central Nervous System Diseases/drug therapy/immunology/metabolism
*Myelin Sheath/drug effects
*Neuroimmunomodulation/drug effects/physiology
*Remyelination/drug effects/physiology
Neuroinflammatory Diseases/drug therapy/immunology
*Histamine H1 Antagonists/pharmacology/therapeutic use

@article {pmid42843275,
year = {2026},
author = {Adrita, N and Claassen, I and Huerta, M and Black, SM and Estevez, AG and Roberts, BR and Beckman, JS and Franco, MC},
title = {Tyrosine nitration: An emerging mechanistic landscape in neurodegeneration and cardiopulmonary disease.},
journal = {Redox biology},
volume = {97},
number = {},
pages = {104423},
doi = {10.1016/j.redox.2026.104423},
pmid = {42843275},
issn = {2213-2317},
abstract = {Protein tyrosine nitration is a post-translational modification associated with conditions of oxidative and inflammatory stress, driven by the production of reactive oxygen and nitrogen species (ROS and RNS). Once considered primarily a footprint of oxidative damage, tyrosine nitration is increasingly recognized as a selective modification that, in specific biological contexts, can alter protein structure, stability, enzymatic activity, and interaction networks. Mechanistically, nitration occurs through peroxynitrite-dependent and heme-peroxidase-dependent pathways and preferentially targets specific tyrosine residues based on local protein structure, solvent accessibility, and microenvironmental chemistry. Accumulating evidence has identified disease-specific nitration signatures across multiple pathological contexts. In neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, nitration of proteins such as tau, α-synuclein, manganese superoxide dismutase, ATP synthase, glyceraldehyde-3-phosphate dehydrogenase, heat shock proteins, and cytoskeletal components contributes to mitochondrial dysfunction, protein aggregation, metabolic failure, and neuronal loss. Similarly, in cardiovascular and pulmonary diseases, protein tyrosine nitration disrupts vascular and epithelial homeostasis by impairing endothelial signaling, fibrinolysis, lipid metabolism, and barrier integrity through modification of key regulatory proteins. By influencing phosphorylation-dependent signaling, enzymatic function, and protein-protein interactions, tyrosine nitration contributes to the connection between redox imbalance and progressive cellular and tissue dysfunction. This review summarizes current mechanistic insights into site-specific protein tyrosine nitration, highlights the emerging disease-associated nitroproteome, and discusses how advances in analytical and structural approaches are redefining nitration as a functional regulatory modification. Understanding the molecular determinants and consequences of tyrosine nitration may enable the development of targeted diagnostics and therapeutic strategies across diverse human diseases.},
}

@article {pmid42844308,
year = {2026},
author = {Gandhi, SM and Patel, S and Haswani, NG and Wahab, S and Sabah, ZU and Kapoor, DU},
title = {RVG29-functionalized nanocarriers for brain-targeted therapy of neurodegenerative diseases: mechanisms, therapeutic advances, and translational perspectives.},
journal = {Naunyn-Schmiedeberg's archives of pharmacology},
volume = {},
number = {},
pages = {},
pmid = {42844308},
issn = {1432-1912},
abstract = {Neurodegenerative diseases (NDs) affect more than 55 million people worldwide, with this number projected to exceed 139 million by 2050 due to population aging. Alzheimer's disease (AD) accounts for 60-70% of dementia cases, while Parkinson's disease (PD) affects over 10 million individuals globally, highlighting the growing clinical and socioeconomic burden of these progressive neurological disorders. Effective treatment of AD, PD, amyotrophic lateral sclerosis (ALS), and related central nervous system disorders remains hindered by the blood-brain barrier (BBB), poor brain accumulation, rapid systemic clearance, and off-target toxicity. RVG29, a 29-amino-acid peptide derived from rabies virus glycoprotein, has emerged as a promising brain-targeting ligand because of its high affinity for nicotinic acetylcholine receptors expressed on neuronal and brain endothelial cells. This review critically examines the mechanisms underlying RVG29-mediated receptor-dependent BBB transcytosis, intracellular trafficking, and neuronal uptake. Furthermore, it comprehensively evaluates RVG29-functionalized lipid nanoparticles, polymeric nanoparticles, exosomes, biomimetic nanocarriers, micelles, inorganic nanostructures, and hybrid systems with respect to their physicochemical characteristics, targeting efficiency, therapeutic efficacy, and safety. Collectively, these nanocarriers demonstrate enhanced BBB penetration, increased drug accumulation in diseased brain regions, and efficient delivery of small molecules, genes, mRNA, and siRNA. By modulating oxidative stress, neuroinflammation, protein aggregation, ferroptosis, and mitochondrial dysfunction, RVG29-engineered nanocarriers provide significant neuroprotection with favorable biocompatibility and minimal immunogenicity. Despite these advances, challenges related to large-scale manufacturing, peptide stability, regulatory approval, and long-term biosafety must be addressed to facilitate their clinical translation as precision neurotherapeutics.},
}

@article {pmid40947692,
year = {2026},
author = {Manubolu, K and Peeriga, R},
title = {Revolutionizing Neurodegenerative Disease Management: The Synergy of AI and Pharmacy.},
journal = {Current aging science},
volume = {19},
number = {3},
pages = {285-302},
pmid = {40947692},
issn = {1874-6128},
mesh = {Humans ; *Artificial Intelligence ; *Neurodegenerative Diseases/drug therapy/diagnosis/genetics ; *Precision Medicine ; Drug Discovery ; Medication Adherence ; Drug Repositioning ; },
abstract = {Neurodegenerative diseases, including Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis (ALS), represent major healthcare challenges worldwide. Despite advances in diagnosis and treatment, these conditions remain incurable, and there is a need for more effective management strategies. The integration of artificial intelligence (AI) in healthcare has emerged as a promising solution, offering new approaches to diagnosis, personalized treatment, and patient care. This paper explores the potential of AI to revolutionize the management of neurodegenerative diseases, with a focus on its synergistic role in pharmacy. By leveraging AI in drug discovery, personalized treatment plans, and clinical decision-making, AI can enhance therapeutic outcomes and improve patient quality of life. The study reviews the current landscape of AI applications in neurodegenerative disease management, with a focus on pharmacy-related interventions. The review includes AI-driven approaches in genomics, biomarkers, drug repurposing, and clinical trials. It also examines AI's role in optimizing pharmaceutical care, improving medication adherence, and tailoring treatments based on individual genetic profiles. AI has demonstrated its capability to analyze vast datasets, from genetic information to clinical records, to identify novel drug targets and predict patient responses to specific therapies. The use of AI in precision medicine has enabled more accurate diagnosis and has facilitated the development of personalized treatments for neurodegenerative diseases. Additionally, AI tools are enhancing medication management by providing personalized therapy adjustments and improving adherence. AI offers transformative potential for the future of neurodegenerative disease management. Its integration into pharmacy practice promises more effective, individualized treatments, accelerating drug discovery, and optimizing patient care. As AI technologies continue to advance, their role in managing complex neurological disorders will become increasingly vital.},
}

Humans
*Artificial Intelligence
*Neurodegenerative Diseases/drug therapy/diagnosis/genetics
*Precision Medicine
Drug Discovery
Medication Adherence
Drug Repositioning

@article {pmid42649099,
year = {2026},
author = {, and Kassardjian, CD and Desai, U and Živković, SA and Simmons, Z and Narayanaswami, P},
title = {It's Virtually Here: Telemedicine, Virtual Care, and Neuromuscular Disease.},
journal = {Muscle & nerve},
volume = {74},
number = {5},
pages = {1318-1327},
doi = {10.1002/mus.70382},
pmid = {42649099},
issn = {1097-4598},
mesh = {Humans ; *Neuromuscular Diseases/therapy/diagnosis ; *Telemedicine/trends ; *COVID-19/epidemiology ; Digital Health ; SARS-CoV-2 ; },
abstract = {The COVID-19 pandemic forced a partial shift in neuromuscular clinical practice away from in-person care to remote means. However, this shift was unexpected, abrupt, reactive to the emergency of a pandemic, and disruptive to the usual manner of care, without adequate time to adapt or study the optimal manner to provide care remotely. While traditionally associated with hub-and-spoke telemedicine models, the pandemic popularized direct-to-home virtual care, mostly unsupported by on-site examiners or standardized platforms. In chronic neuromuscular disorders such as amyotrophic lateral sclerosis (ALS) and myasthenia gravis (MG), virtual care has demonstrated feasibility, patient satisfaction, and potential cost savings, particularly for geographically or functionally disadvantaged populations. Disease-specific adaptations such as the Myasthenia Gravis Core Exam and wearable-based assessments (e.g., home spirometry, grip strength monitoring, and digital outcome measures) have enabled more structured remote evaluations. However, diagnostic accuracy may be compromised by the inability to perform detailed neurological examinations or electrodiagnostic studies. Equity concerns persist due to variability in digital literacy, internet and digital device access, and socioeconomic status. Post-pandemic, patients with disabilities may continue to benefit in a combined virtual/in-person paradigm of care. More evidence is required to evaluate the impact of virtual care on neuromuscular practice quality of care and outcomes. We outline some of the questions that require further study, hoping to spur research and quality improvement investigations of these new care models.},
}

Humans
*Neuromuscular Diseases/therapy/diagnosis
*Telemedicine/trends
*COVID-19/epidemiology
Digital Health
SARS-CoV-2

@article {pmid42833594,
year = {2026},
author = {Dahlhaus, R and Yalcin, I and Tischer, J and Braun, RJ},
title = {TDP-43 and ALS - what's wrong with my membranes?.},
journal = {Neurobiology of disease},
volume = {},
number = {},
pages = {107630},
doi = {10.1016/j.nbd.2026.107630},
pmid = {42833594},
issn = {1095-953X},
abstract = {In recent years, multiple pathologies of the mRNA binding protein TDP-43 have been linked to the neurodegenerative disease Amyotrophic Lateral Sclerosis (ALS), in which almost 97% of all ALS patients exhibit TDP-43 abnormalities in affected neurons. Typically, neuronal degeneration first affects alpha motor neurons of the spinal cord and the lower brainstem, before the disease progresses to Betz cells, giant neurons of the primary motor cortex, and subsequently spreads into further brain regions. It is just the Betz cells though, which do not show cytosolic TDP-43 aggregation upon loss of nuclear TDP-43 expression, but instead display membrane defects in organelles such as the Golgi apparatus, the ER and the nuclear envelope. In this review, we will therefore examine connections between TDP-43 and inner membrane systems, with a particular focus on nuclear and the ER membranes. In doing so, we will summarize evidence suggesting that the disease may have an early onset, potentially even prenatally, and describe how interactions between TDP-43 and the lipid metabolism as well as connections with membrane components, may drive cells towards ALS as time goes by.},
}

@article {pmid42837018,
year = {2026},
author = {de Azevedo, EM and Bernardo, VS and Lima, MMS and Eleutherio, ECA and Outeiro, TF},
title = {SOD1 co-pathologies in the brain: insights from neuropathological evidence and implications.},
journal = {Acta neuropathologica},
volume = {152},
number = {1},
pages = {},
pmid = {42837018},
issn = {1432-0533},
support = {001//Coordenação de Aperfeiçoamento de Pessoal de Nível Superior/ ; 88887.169657/2025-00//Coordenação de Aperfeiçoamento de Pessoal de Nível Superior/ ; 88881.986154/2024-01//Coordenação de Aperfeiçoamento de Pessoal de Nível Superior/ ; 300367/2026-0//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; 309635/2023-3//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; 210.034/2026//Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro/ ; },
mesh = {Humans ; *Superoxide Dismutase-1/metabolism ; *Brain/pathology/metabolism ; *Neurodegenerative Diseases/pathology/metabolism ; Animals ; Amyotrophic Lateral Sclerosis/pathology ; },
abstract = {Superoxide dismutase 1 (SOD1), originally regarded as an antioxidant enzyme, is now recognized as a multifunctional protein whose conformational instability and aggregation contribute to neurodegeneration. The emerging evidence suggests that SOD1 pathology extends beyond amyotrophic lateral sclerosis, supporting a role in multiple neurodegenerative diseases. This review summarizes current neuropathological evidence of SOD1 co-pathologies in the human brain, with particular emphasis on its associations with TAR DNA-binding protein 43 (TDP-43), tau, alpha-synuclein, amyloid-β, and other aggregation-prone proteins. We examine the distribution of pathological SOD1 species across neurodegenerative diseases, their coexistence in affected brain regions, and potential mechanisms underlying these interactions, including oxidative stress, impaired proteostasis, aberrant phase separation, and cross-seeding. We also discuss emerging observations of SOD1 pathology in neurological conditions beyond classical neurodegenerative diseases, raising the possibility that SOD1 misfolding represents a broader cellular response to neuronal injury. Collectively, the available evidence supports a shift from viewing SOD1 as a disease-specific protein to considering it a potential participant in interconnected proteopathic networks. Although the functional significance of SOD1 co-pathologies remains incompletely understood, elucidating the molecular basis of aggregation may provide new insights into disease onset and progression, improving our understanding of neurodegenerative mechanisms, and facilitating the development of biomarkers and the identification of therapeutic targets across diverse proteinopathies.},
}

Humans
*Superoxide Dismutase-1/metabolism
*Brain/pathology/metabolism
*Neurodegenerative Diseases/pathology/metabolism
Animals
Amyotrophic Lateral Sclerosis/pathology

@article {pmid42840744,
year = {2026},
author = {Mouraux, C and Santana, MM and Rosenthal, LS and Cortese, A and Santorelli, FM and Opal, P and Coarelli, G},
title = {The role of neurofilament light chain and other fluid biomarkers in cerebellar ataxias.},
journal = {Brain communications},
volume = {8},
number = {5},
pages = {fcag313},
pmid = {42840744},
issn = {2632-1297},
abstract = {The genetic and phenotypic heterogeneity of hereditary ataxias complicates the design of clinical trials since each ataxia progresses at different rates. Consequently, robust biomarkers are urgently needed to monitor therapeutic efficacy and safety of potential therapeutic interventions. Neurofilament light chain has emerged as a leading candidate, serving as a sensitive pharmacodynamic biomarker of neuronal injury and treatment response in neurodegenerative disorders. This review explores the utility of neurofilament light chain across various ataxias, including polyglutamine spinocerebellar ataxias, Friedreich's ataxia, multiple system atrophy, and other genetic ataxias, such as ataxias associated with RCF1 and SPG7 genes. We synthesize evidence from recent studies that have used ultra-sensitive assays. These studies consistently demonstrate elevated neurofilament light chain levels in cerebrospinal fluid and blood, correlating with disease severity, progression and neuroimaging findings. Notably, neurofilament light chain levels rise during the presymptomatic stage in spinocerebellar ataxias, highlighting its potential for stratifying individuals for trial enrolment and tracking therapeutic effects. A treatment-induced reduction in neurofilament light chain could function as a surrogate endpoint for target engagement, analogous to its validated use in amyotrophic lateral sclerosis. Finally, we discuss the results of other studies conducted on other biomarkers, including glial fibrillary acidic protein, total tau and phosphorylated tau, which may reflect complementary aspects of neurodegeneration and glial activation. Glial fibrillary acidic protein may provide insights into astroglial reactivity and neuroinflammation. Similarly, alteration in total tau and phosphorylated tau levels may suggest dysfunction in neuronal cytoskeleton and axonal integrity. The review also focuses on target-engagement biomarkers, including polyglutamine-expanded ataxin proteins in spinocerebellar ataxias and frataxin in Friedreich's ataxia, as critical tools to complement the ataxia biomarker toolkit. The quantification of mutant ataxin proteins provides a mechanistic readout for emerging gene-silencing or protein-lowering therapies. In parallel, the measurement of frataxin levels serves as a pharmacodynamic marker in therapeutic strategies aiming to restore frataxin expression. These target-engagement biomarkers are valuable in early phases of clinical trials, which mainly aim to demonstrate the biological activity of a treatment before later-phase trials assessing clinical efficacy. Finally, we report on somatic instability in polyglutamine spinocerebellar ataxias as an emerging and highly relevant therapeutic target. CAG repeat mosaicism is gene specific and correlates with disease progression. Integrating measures of repeat instability with neurodegenerative biomarkers could provide a comprehensive monitoring approach in clinical studies. This overview underscores the potential of fluid biomarkers, particularly neurofilament light chain, in accelerating therapeutic development for hereditary ataxias.},
}

@article {pmid42826718,
year = {2026},
author = {Cha, Y and Kim, KS},
title = {From patient cells to patient therapy: Twenty years of iPSC-based translation in neurodegenerative disease.},
journal = {Cell reports. Medicine},
volume = {},
number = {},
pages = {103104},
doi = {10.1016/j.xcrm.2026.103104},
pmid = {42826718},
issn = {2666-3791},
abstract = {Twenty years after the discovery of induced pluripotent stem cells, the field has progressed from patient-specific disease modeling toward cell-based therapies for neurodegenerative disorders. Parkinson's disease has emerged as the leading model for neuronal replacement, whereas Huntington's disease, Alzheimer's disease, and amyotrophic lateral sclerosis require distinct combinations of circuit reconstruction, cellular support, immune modulation, and engineered therapeutic delivery. We discuss key determinants of clinical translation, including cell source, product identity, graft composition, graft-host interactions, manufacturing reproducibility, genomic integrity, and clinical evaluation. We propose that the interval between cell transplantation and long-term engraftment constitutes a biological "black box" in which graft fate and therapeutic outcome are determined. As regenerative medicine enters its third decade, future progress will depend not only on generating therapeutic cells but also on elucidating and engineering the biological processes that determine their fate after transplantation, marking a conceptual transition from stem cell biology toward transplantation biology.},
}

@article {pmid42826647,
year = {2026},
author = {Esmaeili, H and Das, S and Rytel, K and Sidransky, E and Chen, Y},
title = {CRISPR screening in neurodegeneration and lysosomal biology: Uncovering disease mechanisms and genetic modifiers.},
journal = {Molecular genetics and metabolism},
volume = {149},
number = {3},
pages = {110265},
doi = {10.1016/j.ymgme.2026.110265},
pmid = {42826647},
issn = {1096-7206},
abstract = {Growing genetic and mechanistic evidence has highlighted substantial convergence between neurodegenerative disorders and lysosomal biology. Variants in lysosomal protein-encoding genes associated with lysosomal storage disorders (LSDs) have been implicated in common neurodegenerative diseases, suggesting that perturbations of lysosomal function represent a shared pathogenic mechanism. However, the low penetrance of neurodegenerative diseases in individuals carrying variants in these lysosomal genes suggests that additional genetic modifiers are involved as well. Advances in functional genomics, particularly clustered regularly interspaced short palindromic repeat (CRISPR)-based high-throughput screens, have opened new avenues to identify such modifiers and elucidate disease-associated pathways. These unbiased approaches have accelerated the discovery of molecular mechanisms underlying neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Although to date few studies have applied CRISPR-based functional screens directly to LSDs, findings from neurodegenerative disease models provide a valuable framework for investigating lysosomal pathways and identifying genetic factors that influence phenotypic variability. In this review, we summarize recent advances in in vitro CRISPR-based screening approaches in neurodegenerative disorders and discuss their implications for understanding lysosomal biology and LSD-related mechanisms.},
}

@article {pmid41762671,
year = {2026},
author = {Gaur, N and Angerer, C and Gunes, ZI and Ancau, M and Wang, M and Riemenschneider, H and Hurler, CA and Mungwa, S and Lüningschrör, P and Zhiti, A and Steinbach, R and Briese, M and Srivastava, M and Plaas, M and Hermann, A and Sendtner, M and Jäkel, S and Edbauer, D and Herms, J and Liebscher, S and Grosskreutz, J and Brill, MS},
title = {Constitutive neuronal expression and disease-associated upregulation of chitinases in amyotrophic lateral sclerosis.},
journal = {Brain : a journal of neurology},
volume = {149},
number = {10},
pages = {3457-3474},
doi = {10.1093/brain/awag083},
pmid = {41762671},
issn = {1460-2156},
support = {//German Ministry for Education and Research/ ; //JPND/ ; 01ED1202B//SOPHIA/ ; 01ED15511A//SOPHIA/ ; //E-RARE/ ; 01GM1304//PYRAMID/ ; //Boris Canessa foundation/ ; 450131873//Deutsche Forschungsgemeinschaft/ ; ANR-21-CE37-0033-01//Deutsche Forschungsgemeinschaft/ ; 413668513//Deutsche Forschungsgemeinschaft/ ; 390857198//Excellence Cluster SyNergy/ ; //Deutsche Gesellschaft für Muskelkranke/ ; //Friedrich Schiller University/ ; PSG471//Estonian Research Council/ ; //Transregional Collaborative Research Centre/ ; //The Graduate School of Systemic Neurosciences/ ; //Agence Nationale de la Recherche/ ; //German Research Foundation/ ; //Hermann and Lilly Schilling Stiftung für medizinische Forschung im Stifterverband/ ; },
mesh = {*Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology/enzymology ; Humans ; *Chitinases/metabolism/genetics/biosynthesis ; Animals ; Up-Regulation ; *Neurons/metabolism/enzymology ; Mice ; Chitinase-3-Like Protein 1/metabolism ; Hexosaminidases/metabolism ; Female ; Mice, Transgenic ; Male ; },
abstract = {Chitinases are hydrolytic enzymes responsible for degrading chitin and have been evolutionarily conserved across various species. Although their signalling pathways are not fully understood, the chitinases are considered active immunomodulators across several cell types. Specific isoforms, including chitotriosidase-1 (CHIT1), chitinase-3-like protein 1 (CHI3L1), and human-specific chitinase-3-like protein 2 (CHI3L2), have emerged as markers of inflammation across the neurodegenerative spectrum, including amyotrophic lateral sclerosis (ALS). ALS is a fatal neuromuscular condition, and therapeutic development has been severely hindered by phenotypic heterogeneity and an incomplete understanding of aetiology. Although several overlapping disease mechanisms can contribute to neuronal death, inflammation can exacerbate pathology. Prior studies have reported that CHIT1, CHI3L1 and CHI3L2 levels are elevated in the CSF of ALS patients and associated with disease aggressiveness. Nevertheless, several open questions critical to our understanding of the role of chitinases in ALS disease burden remain: namely, (i) which cell types in the CNS are chitinase sources under physiological conditions; (ii) which of these display chitinase upregulation in ALS; and (iii) what is the diagnostic utility of the chitinases relative to established biomarkers. Here, we utilize preclinical models and post-mortem human tissue to demonstrate at both the transcriptomic and protein level that neurons are a primary source of chitinases; furthermore, neuronal chitinase expression is conserved across species. Under physiological conditions, CHI3L1 is more abundant and widely expressed across various cell types, whereas CHIT1 is predominantly expressed in neurons. Additionally, utilizing symptomatic mice from three familial ALS models, we demonstrate isoform-specific expression profiles, with astroglial and microglial upregulation of CHI3L1, and neuronal and microglial upregulation of CHIT1. Differing expression dynamics and diagnostic utility were also noted in our clinical cohort: CSF CHIT1 and CHI3L2 levels had more discriminatory power when distinguishing between ALS versus non-ALS controls, while CHI3L1 was more closely associated with inflammation and ageing across the neurodegenerative spectrum. Although the chitinases did not diagnostically outperform the neurofilament proteins, we posit that their expression profiles can inform the optimization of biomarker-guided trial design. Taken together, we demonstrate that chitinase upregulation in ALS is evident in various CNS cell types and that its neuronal expression may provide new insights into its role in disease activity.},
}

*Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology/enzymology
Humans
*Chitinases/metabolism/genetics/biosynthesis
Animals
Up-Regulation
*Neurons/metabolism/enzymology
Mice
Chitinase-3-Like Protein 1/metabolism
Hexosaminidases/metabolism
Female
Mice, Transgenic
Male

@article {pmid42012311,
year = {2026},
author = {Erol, ZY and Quintanilla, C and Ozdinler, PH},
title = {Bringing cellular clarity to the cortical component of ALS with a high-density multi-electrode array system.},
journal = {The FEBS journal},
volume = {293},
number = {19},
pages = {5686-5695},
pmid = {42012311},
issn = {1742-4658},
support = {R01 AG061708/AG/NIA NIH HHS/United States ; R01AG061708//NIH-NIA/ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology/physiopathology/metabolism ; Microelectrodes ; Animals ; *Single-Cell Analysis/methods/instrumentation ; Neurons/pathology ; },
abstract = {There is selective vulnerability in diseases, requiring the understanding of cell-type specific aspects of neurodegeneration with cellular resolution. Single-cell electrophysiology enables direct investigation of neuronal excitability, ion-channel dynamics, and synaptic transmission with high temporal precision, which is crucial in understanding neuronal circuitries and how they are affected in diseases. Microelectrode arrays (MEAs) have emerged as powerful platforms enabling long-term, parallel, and non-invasive extracellular measurements. The advent of complementary-metal-oxide-semiconductor (CMOS)-based and high-density microelectrode arrays (HD-MEAs) has expanded the spatial and temporal resolution attainable both in vitro and ex vivo. Combined with acute slices, novel cell-culture approaches and three-dimensional (3D) brain organoids, these tools now expedite translational research in disease modeling, neurotoxicity, and pharmacology. Here, we summarise the significance of single-cell electrophysiology, the advantages of the MEA systems, and the latest biomedical and technological advances in this area of research.},
}

Humans
*Amyotrophic Lateral Sclerosis/pathology/physiopathology/metabolism
Microelectrodes
Animals
*Single-Cell Analysis/methods/instrumentation
Neurons/pathology

@article {pmid42817633,
year = {2026},
author = {Morley, JF},
title = {Proteostasis (in)action: the role of co-pathologies in neurodegenerative disease.},
journal = {Philosophical transactions of the Royal Society of London. Series B, Biological sciences},
volume = {381},
number = {1960},
pages = {},
pmid = {42817633},
issn = {1471-2970},
mesh = {*Proteostasis ; Humans ; *Neurodegenerative Diseases/physiopathology/pathology ; Animals ; Proteotoxic Stress ; Protein Folding ; },
abstract = {Clinically distinct neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS), share in common progressive neuronal dysfunction and cell death associated with the accumulation of misfolded proteins. Central to these processes are the cellular and organismal proteostasis networks responsible for maintaining protein homeostasis through coordinated actions of molecular chaperones, the ubiquitin-proteasome system and autophagy-lysosomal pathways. As a consequence of ageing, genetic modifications and other disease-specific conditions, the proteostatic network becomes compromised, leading to the accumulation of toxic protein aggregates that disrupt neuronal function and lead to neurodegeneration. Specific misfolded proteins are associated with each neurodegenerative disease (i.e. α-synuclein in PD, amyloid-β/tau in AD and TAR DNA-binding protein 43/SOD in ALS). However, increasing evidence implicates more complex interactions of co-pathologies across these disorders, as Lewy bodies are common in AD brains and Alzheimer pathology is present in the majority of PD autopsy cases. These observations are consistent with the idea that disruption of proteostasis networks by one aggregation-prone protein could result in misfolding and aggregation of other neurodegeneration-related species. This review will examine the characteristics and consequences of co-pathologies in neurodegenerative disorders. Additionally, the review will outline emerging therapeutic strategies targeted at restoring proteostasis and mitigating the effects of co-pathological processes associated with neurodegenerative diseases. This article is part of the Theo Murphy meeting issue 'ProteostaSys: a systems view of proteostasis'.},
}

*Proteostasis
Humans
*Neurodegenerative Diseases/physiopathology/pathology
Animals
Proteotoxic Stress
Protein Folding

@article {pmid42825562,
year = {2026},
author = {Bromberg, MB},
title = {Amyotrophic Lateral Sclerosis.},
journal = {Continuum (Minneapolis, Minn.)},
volume = {32},
number = {5},
pages = {1529-1544},
doi = {10.1212/cont.0000000000001753},
pmid = {42825562},
issn = {1538-6899},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/therapy/genetics/physiopathology ; Female ; Male ; Middle Aged ; },
abstract = {OBJECTIVE: This article describes the nerve loss underlying amyotrophic lateral sclerosis, its clinical manifestations, examination findings leading to the diagnosis, the expanding role of genetics, and available treatment and patient management.

LATEST DEVELOPMENTS: The cause of neuron death in patients with amyotrophic lateral sclerosis is not known, but many genes are strongly linked to the disease, in both patients with a family history and those with no history. A multistep pathologic process helps to explain the onset of symptoms later in life, even in patients with associated genes. Posttranslational and epigenetic changes are also important factors. Current clinical trials are based on putative pathologic mechanisms, and some newer therapies are gene-based.

ESSENTIAL POINTS: Amyotrophic lateral sclerosis has distinctive features and can be diagnosed largely from the history and examination, and true mimics are rare. While the cause of neuronal death is not known, pathogenic and risk factor gene variations are present in a number of patients, and posttranscriptional and epigenetic changes are likely major causative factors. Environmental factors likely contribute, but specific avoidable factors have not been identified. Drugs to slow the progress of the disease are currently limited, but trials for all patients with amyotrophic lateral sclerosis continue, including a focus on genetic factors. Patient management is optimized in multidisciplinary amyotrophic lateral sclerosis clinics, and interventions for nutrition with gastric feeding tubes and respiratory insufficiency by noninvasive ventilation enhance patient comfort.},
}

Humans
*Amyotrophic Lateral Sclerosis/diagnosis/therapy/genetics/physiopathology
Female
Male
Middle Aged

@article {pmid42826575,
year = {2026},
author = {Tripathi, A and Yadav, AK and Kumar, N},
title = {AI-driven transcriptomics for neurodegenerative disease research: A systematic review.},
journal = {Computational biology and chemistry},
volume = {126},
number = {Pt 1},
pages = {109448},
doi = {10.1016/j.compbiolchem.2026.109448},
pmid = {42826575},
issn = {1476-928X},
abstract = {BACKGROUND: Neurodegenerative diseases (NDDs), including Alzheimer's disease (AD), Parkinson's disease (PD), and Amyotrophic Lateral Sclerosis (ALS), present a growing global health challenge, with traditional diagnostic and therapeutic approaches facing significant limitations in early detection and mechanistic resolution.

OBJECTIVES: Innovations in transcriptomic technologies-spanning bulk RNA sequencing, single-cell RNA-seq (scRNA-seq), and spatially resolved transcriptomics-provide unprecedented insights into cellular heterogeneity and microenvironmental dysregulation. This systematic review synthesizes recent applications of artificial intelligence (AI), machine learning (ML), and deep learning (DL) across transcriptomic tiers to benchmark computational models for biomarker identification, disease diagnosis, patient subtyping, and drug repurposing.

METHODS & ELIGIBILITY: Following PRISMA 2020 guidelines for qualitative systematic reviews, literature published between 2016 and 2025 was systematically searched across PubMed/MEDLINE, IEEE Xplore, Google Scholar, and bioRxiv/medRxiv. Of 1058 records identified, 19 core empirical studies met all eligibility criteria and were synthesized in depth alongside contextual reference benchmarks.

SYNTHESIS & KEY FINDINGS: Traditional ML algorithms (SVM, RF, Elastic Net) demonstrate high diagnostic accuracy (AUC 0.72-0.98) in blood-based biomarker selection, while deep architectures (autoencoders, LSTMs, and Graph Neural Networks) excel at modeling continuous disease trajectories and resolving spatial transcriptomic niches (e.g., STAGATE, SpaGCN, cell2location). Emerging spatial deep learning models successfully localize disease-associated microglia (DAM) around amyloid plaques and trace axonal degeneration pathways.

LIMITATIONS & CONCLUSIONS: Key translational hurdles include data scarcity in rare NDD subtypes, lack of cross-platform spatial benchmarks, and the black-box nature of deep neural networks. Integrating explainable AI (XAI) and prospective multi-modal cohorts is essential for translating computational transcriptomics into clinical diagnostics and targeted therapeutics.},
}

@article {pmid42826598,
year = {2026},
author = {Rava, A and Di Trapano, M and Tse, C and Ji, L and Bid, HK and Trezza, V},
title = {Acidic cannabinoids in brain disorders: Neurobiological mechanisms, preclinical evidence, and translational challenges.},
journal = {Neuroscience and biobehavioral reviews},
volume = {191},
number = {},
pages = {107005},
doi = {10.1016/j.neubiorev.2026.107005},
pmid = {42826598},
issn = {1873-7528},
abstract = {Acidic cannabinoids, including tetrahydrocannabinolic acid (THCA), cannabidiolic acid (CBDA), cannabigerolic acid (CBGA), and related biosynthetic precursors, represent the predominant phytocannabinoid forms naturally produced by Cannabis sativa. Long considered pharmacologically inactive intermediates, these compounds are now increasingly recognized as bioactive molecules with potential therapeutic relevance for brain disorders. Compared with their decarboxylated counterparts, acidic cannabinoids exhibit distinct physicochemical, pharmacokinetic, and pharmacodynamic properties that may confer reduced psychotropic liability together with unique neurobiological effects. Emerging preclinical evidence indicates that acidic cannabinoids modulate multiple processes implicated in neurological and psychiatric disorders, including serotonergic and endocannabinoid signaling, neuroinflammation, oxidative stress, mitochondrial dysfunction, calcium dyshomeostasis, and synaptic transmission. In this review, we critically examine current knowledge regarding acidic cannabinoids in the context of brain disorders. We first summarize their biosynthesis, chemical stability, pharmacokinetic characteristics, and pharmacological differences from neutral cannabinoids. We then examine preclinical evidence supporting their potential therapeutic effects in epilepsy, anxiety, depression, psychosis-related conditions, and neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. We also discuss how artificial intelligence and computational approaches may support target identification, formulation optimization, pharmacokinetic modeling, and the development of personalized cannabinoid-based interventions. Finally, we highlight key methodological and translational challenges limiting the field and outline priorities for future research. Overall, acidic cannabinoids emerge as promising but still underexplored multitarget compounds with potential relevance for the treatment of brain disorders.},
}

@article {pmid42811116,
year = {2026},
author = {Brooker, SM and Coukos, R and Krainc, D},
title = {Lysosomal dysfunction in neurodegenerative disease.},
journal = {Nature reviews. Neurology},
volume = {},
number = {},
pages = {},
pmid = {42811116},
issn = {1759-4766},
abstract = {Examination of genetic risk factors associated with neurodegenerative diseases has provided important mechanistic insights into the pathophysiology of these disorders, and it has implicated defects in lysosomal function as a key component of the neurodegenerative process. The lysosome has a primary role in mediating degradation of both intracellular contents and endocytosed material from the extracellular space. Aggregation of misfolded proteins is a pathological mechanism that is observed across neurodegenerative disorders, and aberrant lysosomal degradation of such proteins plays a pivotal part in driving neuronal dysfunction and cell loss. In addition to the crucial role of the endolysosomal system in degradation of intracellular constituents, lysosomes also serve as important nodes for intracellular signalling, participating in nutrient sensing, lipid metabolism, membrane repair and neuroinflammation. In this Review, we provide an overview of mechanisms of lysosomal dysfunction in neurodegenerative disease, with a particular focus on Parkinson disease, Alzheimer disease, frontotemporal dementia and amyotrophic lateral sclerosis.},
}

@article {pmid42812195,
year = {2026},
author = {Tao, R and Zheng, W and Peng, L and Lv, S and Wang, Q},
title = {Multistage pathogenesis and disease associations of Mycobacterium avium subsp. paratuberculosis.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1948490},
pmid = {42812195},
issn = {1664-3224},
mesh = {*Mycobacterium avium subsp. paratuberculosis/pathogenicity/immunology/genetics ; Animals ; *Paratuberculosis/microbiology/immunology/epidemiology/transmission ; Humans ; Macrophages/immunology/microbiology ; Host-Pathogen Interactions ; },
abstract = {Mycobacterium avium subsp. paratuberculosis (MAP) is the primary causative agent of Johne's disease (JD) in ruminants and bears potential public-health implications. Cumulative epidemiological and molecular evidence implies MAP may contribute to Crohn's disease (CD), whereas its links to multiple sclerosis (MS), type 1 diabetes mellitus (T1DM), and amyotrophic lateral sclerosis (ALS) remain associative without proven causality. This narrative review synthesizes MAP environmental distribution, strain genotyping, transmission routes, and multistage pathogenic mechanisms. MAP breaches the intestinal barrier via fibronectin attachment protein (FAP)-mediated invasion of microfold cells and establishes intracellular persistence within macrophages. It deploys virulence factors including protein kinase G (PknG) to inhibit phagosome-lysosome fusion, the stringent response regulator RelA for metabolic reprogramming, and the ESX-3 secretion system for iron acquisition, while subverting host immunity through M2 macrophage polarization and interleukin-10 (IL-10)/interleukin-6 (IL-6)-mediated anti-inflammatory responses, ultimately driving chronic granulomatous inflammation and tissue injury. We also critically assess diagnostic limitations-particularly the inability of polymerase chain reaction (PCR) to distinguish viable from non-viable organisms-and highlight major research challenges, including extrapolation of virulence mechanisms from other mycobacterial species. This work provides a theoretical framework for prevention, diagnosis, and targeted intervention of MAP-associated disorders.},
}

*Mycobacterium avium subsp. paratuberculosis/pathogenicity/immunology/genetics
Animals
*Paratuberculosis/microbiology/immunology/epidemiology/transmission
Humans
Macrophages/immunology/microbiology
Host-Pathogen Interactions

@article {pmid42814295,
year = {2026},
author = {Chan, L and Shaikh, FA and Shah, P and Moriyama, H and Yokota, T},
title = {Development and Clinical Applications of Antisense Oligonucleotide Gapmers.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {3065},
number = {},
pages = {19-51},
pmid = {42814295},
issn = {1940-6029},
mesh = {Humans ; *Oligonucleotides, Antisense/therapeutic use/genetics/chemistry ; Animals ; *Genetic Diseases, Inborn/genetics/therapy ; *Genetic Therapy/methods ; },
abstract = {Antisense oligonucleotides (AONs) are synthetic oligonucleotides designed to bind target RNA and have opened new treatment possibilities for genetic diseases by regulating gene expression. AONs are often used to suppress the expression of mutated genes, which may interfere with essential downstream pathways. Since AONs have been introduced for clinical use, different chemistries have been developed to further improve efficacy, potency, and safety. One such chemistry is a chimeric structure of a central block of deoxyribonucleotides flanked by sequences of modified nucleotides. Referred to as a gapmer, this chemistry produced promising results in the treatment of genetic diseases. Tofersen is an example of a recently FDA-approved antisense oligonucleotide gapmer used for the treatment of amyotrophic lateral sclerosis. Many others are being tested in clinical trials or under preclinical development. This chapter will cover advancements in gapmer treatments for various diseases, including familial hypercholesterolemia, hereditary transthyretin amyloidosis, cancer, familial chylomicronemia syndrome, familial partial lipodystrophy, familial hypertriglyceridemia, Huntington's disease, myotonic dystrophy, prion diseases, and amyotrophic lateral sclerosis.},
}

Humans
*Oligonucleotides, Antisense/therapeutic use/genetics/chemistry
Animals
*Genetic Diseases, Inborn/genetics/therapy
*Genetic Therapy/methods

@article {pmid42814303,
year = {2026},
author = {Nakamura, Y and Moriyama, H and Yokota, T},
title = {Development of Antisense Oligonucleotide Gapmers for Amyotrophic Lateral Sclerosis.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {3065},
number = {},
pages = {161-170},
pmid = {42814303},
issn = {1940-6029},
mesh = {*Amyotrophic Lateral Sclerosis/genetics/therapy/metabolism/drug therapy ; Humans ; *Oligonucleotides, Antisense/genetics/therapeutic use/administration & dosage/chemistry ; Animals ; Superoxide Dismutase-1/genetics/metabolism ; Biomarkers ; },
abstract = {Advances in genetics and RNA biology have transformed the therapeutic landscape for neurodegenerative disease. Antisense oligonucleotide (ASO) therapies-particularly RNase H-activating "gapmers"-now enable sequence-specific suppression of pathogenic transcripts in the central nervous system. In amyotrophic lateral sclerosis (ALS), tofersen, a 2'-MOE-modified phosphorothioate ASO targeting SOD1 mRNA, has entered clinical use. By promoting RNase H-mediated degradation of SOD1 transcripts after intrathecal delivery, tofersen lowers SOD1 protein in cerebrospinal fluid and plasma neurofilament light chain, demonstrating robust target engagement and neurodegeneration biomarker improvement. Although pivotal trials did not meet primary functional endpoints (ALSFRS-R) at 28 weeks, longer-term and real-world observations suggest potential clinical benefit with earlier initiation, a hypothesis now being tested in presymptomatic SOD1 variant carriers. This chapter reviews the development of gapmer ASOs for ALS with a focus on tofersen-covering chemistry and mechanism, preclinical validation, clinical efficacy and safety, biomarker readouts, and ongoing trials-while outlining key challenges (CNS delivery, adverse event monitoring, endpoint sensitivity) and future directions, including earlier intervention guided by biomarkers and extension to additional genetic forms of ALS.},
}

*Amyotrophic Lateral Sclerosis/genetics/therapy/metabolism/drug therapy
Humans
*Oligonucleotides, Antisense/genetics/therapeutic use/administration & dosage/chemistry
Animals
Superoxide Dismutase-1/genetics/metabolism
Biomarkers

@article {pmid42809516,
year = {2026},
author = {Jang, K and Morton, RL and Dennis, M and Nikolovski, J and Zhan, X and Ke, Y and Burns, B and Tran, AD},
title = {The cost-effectiveness and health equity of prehospital treatment strategies for out-of-hospital cardiac arrest patients: a systematic review.},
journal = {Prehospital emergency care},
volume = {},
number = {},
pages = {1-66},
doi = {10.1080/10903127.2026.2741269},
pmid = {42809516},
issn = {1545-0066},
abstract = {OBJECTIVES: Out-of-hospital cardiac arrest (OHCA) remains a major public health challenge, associated with substantial mortality and significant costs for health care system. This systematic review aimed to (i) synthesise economic evaluations of prehospital treatment strategies for OHCA from ambulance attendance through to hospital discharge; (ii) assess the methodological quality and reporting of the included studies; and (iii) evaluate the reporting of health equity-relevant data.

METHODS: We searched Medline, Embase, Scopus, EconLit, and CINAHL databases for records from database inception to 12 June 2026. The QHES and CHEERS checklists were used to assess the quality and reporting standards of included studies, and the review was reported according to the PRISMA checklist. The completeness of reporting health equity outcomes was reviewed using the PROGRESS (Place of residence, Race, Occupation, Gender, Religion, Education, Socioeconomic status and Social capital) - Plus framework.

RESULTS: Ten economic evaluations met eligibility criteria. Most studies were cost-utility analyses (n = 8, 80%) and used Markov models (n = 6, 60%). Most evaluations were 'very good quality' (≥80%) (n = 6, 60%). Early defibrillation and advanced life support (ALS) delivered by trained emergency medical technicians were cost-effective compared with no intervention, emergency physician-led ALS, standard emergency medical services or paramedic care (ICER range from £11,407 to USD $56,700 per QALY gained). Prehospital extracorporeal cardiopulmonary resuscitation (ECPR) was more cost-effective than in-hospital ECPR strategies (ICER range from AUD $27,323 to $44,000 per QALY gained). Termination-of-resuscitation (TOR) strategies were cost-effective compared with no TOR or other TOR strategies, including basic life support and ALS TOR, with estimates of $110,554 saved per QALY lost and USD $23,851 per QALY gained.Survival rate and neurological outcomes influenced cost-effectiveness results. Equity reporting was limited: almost all included studies addressed less than 40% of the PROGRESS-Plus equity criteria.

CONCLUSIONS: Most strategies that increased prehospital treatment intensity, avoided futile transport, or enabled earlier advanced care were cost-effective; however, the certainty of evidence, particularly for sub-groups, was limited by heterogeneous comparators and sparse equity reporting.},
}

@article {pmid42805693,
year = {2026},
author = {Li, H and Gao, WY},
title = {Comparison of the catalysis of ThDP-dependent enzymes AHAS, ALS, and DXPS.},
journal = {Methods in enzymology},
volume = {736},
number = {},
pages = {127-156},
doi = {10.1016/bs.mie.2026.07.004},
pmid = {42805693},
issn = {1557-7988},
mesh = {*Acetolactate Synthase/metabolism/chemistry ; *Thiamine Pyrophosphate/metabolism ; Chromatography, High Pressure Liquid/methods ; *Transferases/metabolism/chemistry ; *Enzyme Assays/methods ; Catalysis ; Biocatalysis ; },
abstract = {Thiamine diphosphate (ThDP)-dependent enzymes are primarily classified into lyases, transferases, and oxidoreductases, catalyzing various biologically important reactions such as keto transfer, dehydrogenation, decarboxylation, and stereoselective C-C bond formation/cleavage in chiral natural products biosynthesis. They constitute one of the largest superfamilies of biocatalysts, operate basically in all forms of living systems. In this chapter, the research progress on three ThDP enzymes are reviewed, including acetohydroxyacid synthase (AHAS) which is a key enzyme in the anabolic pathway for the biosynthesis of branched chain amino acids, acetolactate synthase (ALS) that belongs to the catabolic pathway for the biosynthesis of platform compounds acetoin and 2,3-butanediol, and 1-deoxy-D-xylulose-5-phosphate synthase (DXPS) which is a rate-limiting enzyme in the MEP terpenoid biosynthetic pathway and is also involved in the biosynthesis of ThDP and pyridoxal phosphate in certain bacteria, with the emphasis on comparing the catalysis of the three enzymes. Furthermore, two precolumn derivatization-HPLC protocols using 4-nitro-o-phenylenediamine and 2,4-dinitrophenylhydrazine as respective derivatizing reagents are also described in detail. The methods can not only be utilized to measure the activities of the above enzymes, supplementing the deficiencies of the classic spectrophotometry, but also be used to comprehensively elucidate the consumption of the substrate(s) and the formation of the products in the reactions catalyzed by AHAS, ALS, or DXPS.},
}

*Acetolactate Synthase/metabolism/chemistry
*Thiamine Pyrophosphate/metabolism
Chromatography, High Pressure Liquid/methods
*Transferases/metabolism/chemistry
*Enzyme Assays/methods
Catalysis
Biocatalysis

@article {pmid40658257,
year = {2025},
author = {Fasano, A and Vacchiano, V and Bonan, L and McMackin, R and Nasseroleslami, B and Hardiman, O and Liguori, R},
title = {Neurophysiological biomarkers of networks impairment in amyotrophic lateral sclerosis.},
journal = {Journal of neurology},
volume = {272},
number = {8},
pages = {507},
pmid = {40658257},
issn = {1432-1459},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; Biomarkers ; Transcranial Magnetic Stimulation ; *Nerve Net/physiopathology ; Electroencephalography ; Electromyography ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a heterogeneous disease involving motor system as well as cognitive domains. There is an urgent need for objective biomarkers that can subcategorize subjects into homogeneous groups based on disease pathobiology.In this review, we discuss novel neurophysiological techniques that provide detailed, multiscale and multidimensional insights into ALS networks impairment, spanning from the micro-columnar architecture of the motor cortex to motor and cognitive networks. Specifically, Transcranial Magnetic Stimulation (TMS) paradigms can be used to evaluate the status of excitatory and inhibitory networks within the layers of the motor cortex. Abnormalities in functional connectivity between the two motor areas, as well as within the frontal-temporal and frontal parietal networks, can be characterized using novel source-localization analysis of high-density electroencephalography (EEG). TMS and EEG techniques provide data that correlate with both motor and cognitive impairment. Furthermore, cortico-muscular coherence analysis can be used to assess functional dysregulation within the entire motor system, and novel surface electromyography (EMG) techniques, such as motor unit number estimation, motor unit number index, and nerve excitability testing studies provide useful insights into axonal loss and membrane ion channel dysfunctions in lower motor neurons.The integrated analysis of these biomarkers provides valuable insights into the clinical and biologic heterogeneity of the disease, aiding the intelligent design of next generation precision-based therapeutics.},
}

Humans
*Amyotrophic Lateral Sclerosis/physiopathology/diagnosis
Biomarkers
Transcranial Magnetic Stimulation
*Nerve Net/physiopathology
Electroencephalography
Electromyography