@article {pmid40362304,
year = {2025},
author = {Shiryaeva, O and Tolochko, C and Alekseeva, T and Dyachuk, V},
title = {Targets and Gene Therapy of ALS (Part 1).},
journal = {International journal of molecular sciences},
volume = {26},
number = {9},
pages = {},
doi = {10.3390/ijms26094063},
pmid = {40362304},
issn = {1422-0067},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/genetics/pathology ; *Genetic Therapy/methods ; Animals ; Superoxide Dismutase-1/genetics ; C9orf72 Protein/genetics ; Mutation ; Gene Editing ; RNA-Binding Protein FUS/genetics ; Oligonucleotides, Antisense/therapeutic use ; CRISPR-Cas Systems ; DNA-Binding Proteins/genetics ; RNA Interference ; MicroRNAs/genetics ; Disease Models, Animal ; RNA, Small Interfering/genetics ; Motor Neurons/metabolism/pathology ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the selective death of motor neurons, which causes muscle atrophy. Genetic forms of ALS are recorded only in 10% of cases. However, over the past decade, studies in genetics have substantially contributed to our understanding of the molecular mechanisms underlying ALS. The identification of key mutations such as SOD1, C9orf72, FUS, and TARDBP has led to the development of targeted therapy that is gradually being introduced into clinical trials, opening up a broad range of opportunities for correcting these mutations. In this review, we aimed to present an extensive overview of the currently known mechanisms of motor neuron degeneration associated with mutations in these genes and also the gene therapy methods for inhibiting the expression of their mutant proteins. Among these, antisense oligonucleotides, RNA interference (siRNA and miRNA), and gene-editing (CRISPR/Cas9) methods are of particular interest. Each has shown its efficacy in animal models when targeting mutant genes, whereas some of them have proven to be efficient in human clinical trials.},
}

Humans
*Amyotrophic Lateral Sclerosis/therapy/genetics/pathology
*Genetic Therapy/methods
Animals
Superoxide Dismutase-1/genetics
C9orf72 Protein/genetics
Mutation
Gene Editing
RNA-Binding Protein FUS/genetics
Oligonucleotides, Antisense/therapeutic use
CRISPR-Cas Systems
DNA-Binding Proteins/genetics
RNA Interference
MicroRNAs/genetics
Disease Models, Animal
RNA, Small Interfering/genetics
Motor Neurons/metabolism/pathology

@article {pmid40360341,
year = {2025},
author = {Lin, W and Huang, C and Tan, Z and Xu, H and Wei, W and Wang, L},
title = {Cu[II]-bis(thioureido) Complex: A Potential Radiotracer for Detecting Oxidative Stress and Neuroinflammation in Neurodegenerative Diseases.},
journal = {Seminars in nuclear medicine},
volume = {},
number = {},
pages = {},
doi = {10.1053/j.semnuclmed.2025.03.008},
pmid = {40360341},
issn = {1558-4623},
abstract = {Neurodegenerative diseases, characterized by progressive neuronal degeneration and associated with neuroinflammation and oxidative stress, present significant challenges in diagnosis and treatment. This review explores the potential of copper(II)-bis(thiosemicarbazone) complexes, particularly Cu-ATSM, as a dual-purpose radiopharmaceutical for imaging and therapeutic interventions. Cu-ATSM exhibits unique redox-dependent retention in pathological microenvironments, driven by mitochondrial dysfunction and hyper-reductive states, which enables the noninvasive detection of oxidative stress via positron emission tomography (PET). Preclinical studies demonstrate its efficacy in mitigating neuroinflammation by suppressing glial activation, reducing the secretion of pro-inflammatory cytokines (e.g., TNF-α, MCP-1), and increasing the expression of neuroprotective metallothionein-1 (MT1). Some Clinical research reveals elevated [64]Cu-ATSM uptake in Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS) patients, correlating with disease severity and regional oxidative stress markers. Furthermore, Cu-ATSM derivatives show promise in modulating blood-brain barrier (BBB) permeability, enhancing amyloid-β clearance, and restoring copper homeostasis in ALS models. Despite these advances, limitations such as small cohort sizes and heterogeneity in clinical studies underscore the need for larger-scale validation. Multimodal imaging integrating PET and MRI, alongside novel structural analogs targeting Aβ plaques and redox imbalances, emerges as a strategic direction for future research. Collectively, Cu-ATSM represents a transformative tool for elucidating neuropathological mechanisms and advancing therapeutic strategies in neurodegenerative disorders.},
}

@article {pmid40353906,
year = {2025},
author = {Kleinerova, J and Querin, G and Pradat, PF and Siah, WF and Bede, P},
title = {New developments in imaging in ALS.},
journal = {Journal of neurology},
volume = {272},
number = {6},
pages = {392},
pmid = {40353906},
issn = {1432-1459},
support = {JPND-Cofund-2-2019-1/HRBI_/Health Research Board/Ireland ; HRB EIA-2017-019/HRBI_/Health Research Board/Ireland ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/physiopathology/pathology ; *Neuroimaging/methods/trends ; *Brain/diagnostic imaging ; Magnetic Resonance Imaging ; },
abstract = {Neuroimaging in ALS has contributed considerable academic insights in recent years demonstrating genotype-specific topological changes decades before phenoconversion and characterising longitudinal propagation patterns in specific phenotypes. It has elucidated the radiological underpinnings of specific clinical phenomena such as pseudobulbar affect, apathy, behavioural change, spasticity, and language deficits. Academic concepts such as sexual dimorphism, motor reserve, cognitive reserve, adaptive changes, connectivity-based propagation, pathological stages, and compensatory mechanisms have also been evaluated by imaging. The underpinnings of extra-motor manifestations such as cerebellar, sensory, extrapyramidal and cognitive symptoms have been studied by purpose-designed imaging protocols. Clustering approaches have been implemented to uncover radiologically distinct disease subtypes and machine-learning models have been piloted to accurately classify individual patients into relevant diagnostic, phenotypic, and prognostic categories. Prediction models have been developed for survival in symptomatic patients and phenoconversion in asymptomatic mutation carriers. A range of novel imaging modalities have been implemented and 7 Tesla MRI platforms are increasingly being used in ALS studies. Non-ALS MND conditions, such as PLS, SBMA, and SMA, are now also being increasingly studied by quantitative neuroimaging approaches. A unifying theme of recent imaging papers is the departure from describing focal brain changes to focusing on dynamic structural and functional connectivity alterations. Progressive cortico-cortical, cortico-basal, cortico-cerebellar, cortico-bulbar, and cortico-spinal disconnection has been consistently demonstrated by recent studies and recognised as the primary driver of clinical decline. These studies have led the reconceptualisation of ALS as a "network" or "circuitry disease".},
}

Humans
*Amyotrophic Lateral Sclerosis/diagnostic imaging/physiopathology/pathology
*Neuroimaging/methods/trends
*Brain/diagnostic imaging
Magnetic Resonance Imaging

@article {pmid40350993,
year = {2025},
author = {Vedeler, A and Tartaglia, GG and Pastore, A},
title = {Annexin, a Protein for All Seasons: From Calcium Dependent Membrane Metabolism to RNA Recognition.},
journal = {BioEssays : news and reviews in molecular, cellular and developmental biology},
volume = {},
number = {},
pages = {e70019},
doi = {10.1002/bies.70019},
pmid = {40350993},
issn = {1521-1878},
support = {ASTRA_855923//ERC / ; PNRRCN00000041andEPNRRCN3//Piano Nazionale di Ripresa e Resilienza of Italian MUR/ ; IVBM4PAP_101098989//EIC Pathfinder/ ; ARUK_PG2019B-020//ARUK / ; },
abstract = {Annexins are a protein family well known to bind to phospholipids in a calcium-dependent way. They are involved in several different crucial cellular processes such as cell division, calcium signaling, membrane repair, vesicle trafficking, and apoptosis. Although RNA binding for some members of the family was reported long ago, it was only recently that it was shown that a common feature of the family is also the ability to bind RNA, a discovery that has added significantly to our perception of the cellular role of these proteins. In the present review, we discuss the properties of annexins under an updated light and the current knowledge on the RNA binding properties of annexins. We then focus specifically on annexin A11, because this is a less characterized member of the family but, at the same time, a potentially important component of the mRNA transport machinery in neurons. We hope to offer to the reader a more complete picture of the annexins' binding properties and new tools to evaluate the multifaceted functions of this important protein family.},
}

@article {pmid40350723,
year = {2025},
author = {Kuznetsova, DR and Kutlubaev, MA and Pervushina, EV},
title = {[Oculomotor disorders in patients with amyotrophic lateral sclerosis].},
journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova},
volume = {125},
number = {4},
pages = {7-12},
doi = {10.17116/jnevro20251250417},
pmid = {40350723},
issn = {1997-7298},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/physiopathology ; *Ocular Motility Disorders/etiology/physiopathology/diagnosis ; Saccades ; Eye Movements ; },
abstract = {Oculomotor disorders are not typical manifestations of amyotrophic lateral sclerosis (ALS). Occasionally, this disease is associated with vertical gaze paresis, presenting a distinct type as «ALS+progressive supranuclear palsy». Studies using eye-tracking methods have revealed a variety of subclinical oculomotor disorders in this disease. These disorders can manifest as changes in reflex and voluntary saccades, antisaccades, smooth tracking eye movements, and fixations. A significant association between oculomotor disorders and clinical manifestations of ALS was reported. The occurrence of oculomotor disorders indicates the involvement of broader neuroanatomical structures, including the prefrontal cortex and basal ganglia. The lack of consistency in the data from different studies and their limited number emphasize the need for further research in this area.},
}

Humans
*Amyotrophic Lateral Sclerosis/complications/physiopathology
*Ocular Motility Disorders/etiology/physiopathology/diagnosis
Saccades
Eye Movements

@article {pmid40350633,
year = {2025},
author = {Ishiura, H},
title = {[Genetics of Motor Neuron Diseases and Hereditary Spastic Paraplegia].},
journal = {Brain and nerve = Shinkei kenkyu no shinpo},
volume = {77},
number = {5},
pages = {481-491},
doi = {10.11477/mf.188160960770050481},
pmid = {40350633},
issn = {1881-6096},
mesh = {Humans ; *Spastic Paraplegia, Hereditary/genetics/diagnosis/therapy ; *Motor Neuron Disease/genetics/diagnosis ; },
abstract = {Motor neuron diseases encompass a range of phenotypes, including amyotrophic lateral sclerosis (ALS), primary lateral sclerosis (PLS), progressive muscular atrophy (PMA), and spinal muscular atrophy (SMA). Related conditions include spinal and bulbar muscular atrophy (SBMA) and hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P). Hereditary spastic paraplegia (HSP)-a group of disorders primarily affecting the corticospinal tract-also exhibits diverse clinical manifestations. This review summarizes the genetic basis of these diseases, along with their clinical characteristics, diagnostic approaches, and disease-specific therapies.},
}

Humans
*Spastic Paraplegia, Hereditary/genetics/diagnosis/therapy
*Motor Neuron Disease/genetics/diagnosis

@article {pmid40350140,
year = {2025},
author = {Amin, MA and Zehravi, M and Sweilam, SH and Shatu, MM and Durgawale, TP and Qureshi, MS and Durgapal, S and Haque, MA and Vodeti, R and Panigrahy, UP and Ahmad, I and Khan, S and Emran, TB},
title = {Neuroprotective potential of epigallocatechin gallate in Neurodegenerative Diseases: Insights into molecular mechanisms and clinical Relevance.},
journal = {Brain research},
volume = {},
number = {},
pages = {149693},
doi = {10.1016/j.brainres.2025.149693},
pmid = {40350140},
issn = {1872-6240},
abstract = {Neurodegenerative diseases (NDs) such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis pose significant challenges due to their complex pathophysiology and lack of effective treatments. Green tea, rich in the epigallocatechin gallate (EGCG) polyphenolic component, has demonstrated potential as a neuroprotective agent with numerous medicinal applications. EGCG effectively reduces tau and Aβ aggregation in ND models, promotes autophagy, and targets key signaling pathways like Nrf2-ARE, NF-κB, and MAPK. This review explores the molecular processes that underlie EGCG's neuroprotective properties, including its ability to regulate mitochondrial dysfunction, oxidative stress, neuroinflammation, and protein misfolding. Clinical research indicates that EGCG may enhance cognitive and motor abilities, potentially inhibiting disease progression despite absorption and dose optimization limitations. The substance has been proven to slow the amyloidogenic process, prevent protein aggregation, decrease amyloid cytotoxicity, inhibit fibrillogenesis, and restructure fibrils for synergistic therapeutic effects. The review highlights the potential of EGCG as a natural, multi-targeted strategy for NDs but emphasizes the need for further clinical trials to enhance its therapeutic efficacy.},
}

@article {pmid40347374,
year = {2025},
author = {Varshney, V and Gabble, BC and Bishoyi, AK and Varma, P and Qahtan, SA and Kashyap, A and Panigrahi, R and Nathiya, D and Chauhan, AS},
title = {Exploring Exosome-Based Approaches for Early Diagnosis and Treatment of Neurodegenerative Diseases.},
journal = {Molecular neurobiology},
volume = {},
number = {},
pages = {},
pmid = {40347374},
issn = {1559-1182},
abstract = {Neurodegenerative diseases (NDs), like Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and Amyotrophic Lateral Sclerosis (ALS), present an increasingly significant global health burden, primarily due to the lack of effective early diagnostic tools and treatments. Exosomes-nano-sized extracellular vesicles secreted by nearly all cell types-have emerged as promising candidates for both biomarkers and therapeutic agents in NDs. This review examines the biogenesis, molecular composition, and diverse functions of exosomes in NDs. Exosomes play a crucial role in mediating intercellular communication. They are capable of reflecting the biochemical state of their parent cells and have the ability to cross the blood-brain barrier (BBB). In doing so, they facilitate the propagation of pathological proteins, such as amyloid-beta (Aβ), tau, and alpha-synuclein (α-syn), while also enabling the targeted delivery of neuroprotective compounds. Recent advancements in exosome isolation and engineering have opened up new possibilities for diagnostic and therapeutic strategies. These range from the discovery of non-invasive biomarkers to innovative approaches in gene therapy and drug delivery systems. However, challenges related to standardization, safety, and long-term effects must be addressed before exosomes can be translated into clinical applications. This review highlights both the promising potential and the obstacles that must be overcome to leverage exosomes in the treatment of NDs and the transformation of personalized medicine.},
}

@article {pmid40344943,
year = {2025},
author = {Zhou, ZD and Yi, L and Popławska-Domaszewicz, K and Chaudhuri, KR and Jankovic, J and Tan, EK},
title = {Glucagon-like peptide-1 receptor agonists in neurodegenerative diseases: Promises and challenges.},
journal = {Pharmacological research},
volume = {216},
number = {},
pages = {107770},
doi = {10.1016/j.phrs.2025.107770},
pmid = {40344943},
issn = {1096-1186},
abstract = {Glucagon-like peptide-1 (GLP-1) receptor agonists (GRA) belong to a class of compounds that reduce blood glucose and energy intake by simulating actions of endogenous incretin hormone GLP-1 after it is released by the gut following food consumption. They are used to treat type 2 diabetes mellitus (T2DM) and obesity and have systemic effects on various organs, including the brain, liver, pancreas, heart, and the gut. Patients with T2DM have a higher risk of developing neurodegenerative diseases (NDs), including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD), accompanied by more severe motor deficits and faster disease progression, suggesting dysregulation of insulin signaling in these diseases. Experimental studies have shown that GRA have protective effects to modulate neuroinflammation, oxidative stress, mitochondrial and autophagic functions, and protein misfolding. Hence the compounds have generated enormous interest as novel therapeutic agents against NDs. To date, clinical trials have shown that three GRA, exenatide, liraglutide and lixisenatide can improve motor deficits as an add-on therapy in PD patients and liraglutide can improve cognitive function in AD patients. The neuroprotective effects of these and other GRA, such as PT320 (a sustained-released exenatide) and semaglutide, are still under investigation. The dual GLP-1/gastric inhibitory polypeptide (GIP) receptor agonists have been demonstrated to have beneficial effects in AD and PD mice models. Overall, GRA are highly promising novel drugs, but future clinical studies should identify which subsets of patients should be targeted as potential candidates for their symptomatic and/or neuroprotective benefits, investigate whether combinations with other classes of drugs can further augment their efficacy, and evaluate their long-term disease-modifying and adverse effects.},
}

@article {pmid40340943,
year = {2025},
author = {Kellett, EA and Bademosi, AT and Walker, AK},
title = {Molecular mechanisms and consequences of TDP-43 phosphorylation in neurodegeneration.},
journal = {Molecular neurodegeneration},
volume = {20},
number = {1},
pages = {53},
pmid = {40340943},
issn = {1750-1326},
mesh = {Humans ; *DNA-Binding Proteins/metabolism ; Phosphorylation/physiology ; Animals ; *Neurodegenerative Diseases/metabolism ; Amyotrophic Lateral Sclerosis/metabolism ; },
abstract = {Increased phosphorylation of TDP-43 is a pathological hallmark of several neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, the regulation and roles of TDP-43 phosphorylation remain incompletely understood. A variety of techniques have been utilized to understand TDP-43 phosphorylation, including kinase/phosphatase manipulation, phosphomimic variants, and genetic, physical, or chemical inducement in a variety of cell cultures and animal models, and via analyses of post-mortem human tissues. These studies have produced conflicting results: suggesting incongruously that TDP-43 phosphorylation may either drive disease progression or serve a neuroprotective role. In this review, we explore the roles of regulators of TDP-43 phosphorylation including the putative TDP-43 kinases c-Abl, CDC7, CK1, CK2, IKKβ, p38α/MAPK14, MEK1, TTBK1, and TTBK2, and TDP-43 phosphatases PP1, PP2A, and PP2B, in disease. Building on recent studies, we also examine the consequences of TDP-43 phosphorylation on TDP-43 pathology, especially related to TDP-43 mislocalisation, liquid-liquid phase separation, aggregation, and neurotoxicity. By comparing conflicting findings from various techniques and models, this review highlights both the discrepancies and unresolved aspects in the understanding of TDP-43 phosphorylation. We propose that the role of TDP-43 phosphorylation is site and context dependent, and includes regulation of liquid-liquid phase separation, subcellular mislocalisation, and degradation. We further suggest that greater consideration of the normal functions of the regulators of TDP-43 phosphorylation that may be perturbed in disease is warranted. This synthesis aims to build towards a comprehensive understanding of the complex role of TDP-43 phosphorylation in the pathogenesis of neurodegeneration.},
}

Humans
*DNA-Binding Proteins/metabolism
Phosphorylation/physiology
Animals
*Neurodegenerative Diseases/metabolism
Amyotrophic Lateral Sclerosis/metabolism

@article {pmid40340620,
year = {2025},
author = {Shen, D and Liu, A and Yang, X and Liu, Q and Liu, M and Cui, L},
title = {Exploring oculomotor challenges in amyotrophic lateral sclerosis: a comprehensive review.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-7},
doi = {10.1080/21678421.2025.2501690},
pmid = {40340620},
issn = {2167-9223},
abstract = {Traditionally understood as a motor neuron disease, amyotrophic lateral sclerosis (ALS) is now recognized to involve broader neurodegenerative processes, including the oculomotor system. This narrative review summarizes current evidence on oculomotor dysfunction in ALS, with a focus on its relationship to disease-related motor and cognitive impairments. Specifically, the review examines key eye-tracking (ET) metrics, including saccades, smooth pursuit, and fixation, highlighting their potential to reflect both motor and extramotor degeneration. Notably, patients with bulbar-onset ALS exhibit more pronounced oculomotor impairments. By synthesizing findings on the connection between oculomotor dysfunction and cognitive decline, this review underscores the potential of ET as a noninvasive tool for assessing ALS progression. Oculomotor metrics, as part of a broader understanding of ALS's impact on multiple neural networks, may offer valuable insights to refine patient assessment and care strategies, particularly in advanced disease stages.},
}

@article {pmid40333317,
year = {2025},
author = {Simula, ER and Jasemi, S and Cossu, D and Fais, M and Cossu, I and Chessa, V and Canu, M and Sechi, LA},
title = {Human Endogenous Retroviruses as Novel Therapeutic Targets in Neurodegenerative Disorders.},
journal = {Vaccines},
volume = {13},
number = {4},
pages = {},
pmid = {40333317},
issn = {2076-393X},
support = {PNRR-MCNT1-2023-12376993//Ministero della Salute/ ; 2022BP837R//MUR, PRIN 2022/ ; 22//Regione Autonoma Sardegna grant: legge regionale 12 22 December 2022/ ; e.INS Ecosystem of Innovation for Next Generation Sardinia spoke n 5//European Union/ ; },
abstract = {Human Endogenous Retroviruses comprise approximately 8% of the human genome, serving as fragments of ancient retroviral infections. Although they are generally maintained in a silenced state by robust epigenetic mechanisms, specific HERV groups, particularly HERV-W and HERV-K, can become derepressed under specific pathological conditions, thereby contributing to the initiation and progression of neuroinflammatory and neurodegenerative processes. Preclinical studies and clinical trials, such as those investigating monoclonal antibodies, indicate that directly targeting these elements may offer a novel therapeutic strategy. In this review, we provide an overview of HERVs' biology, examine their role in neurodegenerative diseases such as amyotrophic lateral sclerosis, multiple sclerosis, Alzheimer's disease, and Parkinson's disease, and explore their therapeutic prospects, highlighting both the challenges and the potential future research directions needed to translate these approaches into clinical interventions.},
}

@article {pmid40332510,
year = {2025},
author = {Stacchiotti, C and Mazzella di Regnella, S and Cinotti, M and Spalloni, A and Volpe, E},
title = {Neuroinflammation and Amyotrophic Lateral Sclerosis: Recent Advances in Anti-Inflammatory Cytokines as Therapeutic Strategies.},
journal = {International journal of molecular sciences},
volume = {26},
number = {8},
pages = {},
pmid = {40332510},
issn = {1422-0067},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology/immunology ; *Cytokines/therapeutic use/metabolism ; Animals ; *Neuroinflammatory Diseases/drug therapy/metabolism/pathology ; *Anti-Inflammatory Agents/therapeutic use/pharmacology ; Blood-Brain Barrier/metabolism ; Inflammation ; },
abstract = {Neuroinflammation is an inflammatory response occurring within the central nervous system (CNS). The process is marked by the production of pro-inflammatory cytokines, chemokines, small-molecule messengers, and reactive oxygen species. Microglia and astrocytes are primarily involved in this process, while endothelial cells and infiltrating blood cells contribute to neuroinflammation when the blood-brain barrier (BBB) is damaged. Neuroinflammation is increasingly recognized as a pathological hallmark of several neurological diseases, including amyotrophic lateral sclerosis (ALS), and is closely linked to neurodegeneration, another key feature of ALS. In fact, neurodegeneration is a pathological trigger for inflammation, and neuroinflammation, in turn, contributes to motor neuron (MN) degeneration through the induction of synaptic dysfunction, neuronal death, and inhibition of neurogenesis. Importantly, resolution of acute inflammation is crucial for avoiding chronic inflammation and tissue destruction. Inflammatory processes are mediated by soluble factors known as cytokines, which are involved in both promoting and inhibiting inflammation. Cytokines with anti-inflammatory properties may exert protective roles in neuroinflammatory diseases, including ALS. In particular, interleukin (IL)-10, transforming growth factor (TGF)-β, IL-4, IL-13, and IL-9 have been shown to exert an anti-inflammatory role in the CNS. Other recently emerging immune regulatory cytokines in the CNS include IL-35, IL-25, IL-37, and IL-27. This review describes the current understanding of neuroinflammation in ALS and highlights recent advances in the role of anti-inflammatory cytokines within CNS with a particular focus on their potential therapeutic applications in ALS. Furthermore, we discuss current therapeutic strategies aimed at enhancing the anti-inflammatory response to modulate neuroinflammation in this disease.},
}

Humans
*Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology/immunology
*Cytokines/therapeutic use/metabolism
Animals
*Neuroinflammatory Diseases/drug therapy/metabolism/pathology
*Anti-Inflammatory Agents/therapeutic use/pharmacology
Blood-Brain Barrier/metabolism
Inflammation

@article {pmid40280464,
year = {2025},
author = {Gritsiuta, AI and Reep, G and Parupudi, S and Petrov, RV},
title = {Optimizing the management of anastomotic leaks after esophagectomy: a narrative review of salvage strategies and outcomes.},
journal = {Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract},
volume = {29},
number = {7},
pages = {102069},
doi = {10.1016/j.gassur.2025.102069},
pmid = {40280464},
issn = {1873-4626},
abstract = {BACKGROUND: Anastomotic leaks (ALs) after esophagectomy remain a major postoperative complication, leading to increased morbidity, prolonged hospital stays, and higher mortality. Despite advancements in surgical techniques and perioperative care, AL management lacks standardized protocols. This review aimed to evaluate current salvage strategies, including conservative, endoscopic, and surgical approaches, to optimize outcomes and reduce complications.

METHODS: A comprehensive literature search was conducted using PubMed, Scopus, Cochrane Library, and Google Scholar databases to identify studies published between 2000 and 2025 on AL management after esophagectomy. Peer-reviewed clinical trials, guidelines, and expert consensus reports were reviewed, focusing on minimally invasive and surgical interventions, patient outcomes, and emerging treatment strategies.

RESULTS: AL management strategies were classified into 3 primary approaches. Conservative management includes nutritional support, antibiotic therapy, and percutaneous drainage, particularly for contained leaks. Endoscopic interventions, such as self-expanding metal stents and endoscopic vacuum-assisted closure, have shown high success rates, with vacuum-assisted closure achieving superior closure outcomes. Hybrid techniques, including stent-over-sponge and vacuum-assisted closure-stent, are emerging as promising alternatives. Surgical interventions remain the gold standard for severe or refractory leaks with options, including primary repair, esophageal diversion, and delayed conduit reconstruction.

CONCLUSION: A multidisciplinary approach is crucial for optimizing AL management, incorporating enhanced recovery protocols, early risk assessment, and individualized treatment plans. Endoscopic techniques have reduced the need for surgical revisions, but surgical intervention remains necessary for severe cases. Future research should focus on refining treatment algorithms, integrating novel technologies, and establishing standardized guidelines to improve patient survival and quality of life.},
}

@article {pmid40332015,
year = {2025},
author = {Duță, C and Dogaru, CB and Muscurel, C and Stoian, I},
title = {Nanozymes: Innovative Therapeutics in the Battle Against Neurodegenerative Diseases.},
journal = {International journal of molecular sciences},
volume = {26},
number = {8},
pages = {},
doi = {10.3390/ijms26083522},
pmid = {40332015},
issn = {1422-0067},
mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/metabolism ; Oxidative Stress/drug effects ; Animals ; Antioxidants/therapeutic use/chemistry/pharmacology ; *Nanostructures/chemistry/therapeutic use ; Reactive Oxygen Species/metabolism ; },
abstract = {Neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD), represent a significant challenge to global health due to their progressive nature and the absence of curative treatments. These disorders are characterized by oxidative stress, protein misfolding, and neuroinflammation, which collectively contribute to neuronal damage and death. Recent advancements in nanotechnology have introduced nanozymes-engineered nanomaterials that mimic enzyme-like activities-as promising therapeutic agents. This review explores the multifaceted roles of nanozymes in combating oxidative stress and inflammation in neurodegenerative conditions. By harnessing their potent antioxidant properties, nanozymes can effectively scavenge reactive oxygen species (ROS) and restore redox balance, thereby protecting neuronal function. Their ability to modify surface properties enhances targeted delivery and biocompatibility, making them suitable for various biomedical applications. In this review, we highlight recent findings on the design, functionality, and therapeutic potential of nanozymes, emphasizing their dual role in addressing oxidative stress and pathological features such as protein aggregation. This synthesis of current research underscores the innovative potential of nanozymes as a proactive therapeutic strategy to halt disease progression and improve patient outcomes in neurodegenerative disorders.},
}

Humans
*Neurodegenerative Diseases/drug therapy/metabolism
Oxidative Stress/drug effects
Animals
Antioxidants/therapeutic use/chemistry/pharmacology
*Nanostructures/chemistry/therapeutic use
Reactive Oxygen Species/metabolism

@article {pmid40328798,
year = {2025},
author = {Wu, X and Yang, Z and Zou, J and Gao, H and Shao, Z and Li, C and Lei, P},
title = {Protein kinases in neurodegenerative diseases: current understandings and implications for drug discovery.},
journal = {Signal transduction and targeted therapy},
volume = {10},
number = {1},
pages = {146},
pmid = {40328798},
issn = {2059-3635},
support = {32070961//National Natural Science Foundation of China (National Science Foundation of China)/ ; },
mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/enzymology/genetics/pathology ; *Drug Discovery ; *Protein Kinases/genetics/metabolism ; *Protein Kinase Inhibitors/therapeutic use ; Signal Transduction/drug effects/genetics ; Phosphorylation ; Animals ; },
abstract = {Neurodegenerative diseases (e.g., Alzheimer's, Parkinson's, Huntington's disease, and Amyotrophic Lateral Sclerosis) are major health threats for the aging population and their prevalences continue to rise with the increasing of life expectancy. Although progress has been made, there is still a lack of effective cures to date, and an in-depth understanding of the molecular and cellular mechanisms of these neurodegenerative diseases is imperative for drug development. Protein phosphorylation, regulated by protein kinases and protein phosphatases, participates in most cellular events, whereas aberrant phosphorylation manifests as a main cause of diseases. As evidenced by pharmacological and pathological studies, protein kinases are proven to be promising therapeutic targets for various diseases, such as cancers, central nervous system disorders, and cardiovascular diseases. The mechanisms of protein phosphatases in pathophysiology have been extensively reviewed, but a systematic summary of the role of protein kinases in the nervous system is lacking. Here, we focus on the involvement of protein kinases in neurodegenerative diseases, by summarizing the current knowledge on the major kinases and related regulatory signal transduction pathways implicated in diseases. We further discuss the role and complexity of kinase-kinase networks in the pathogenesis of neurodegenerative diseases, illustrate the advances of clinical applications of protein kinase inhibitors or novel kinase-targeted therapeutic strategies (such as antisense oligonucleotides and gene therapy) for effective prevention and early intervention.},
}

Humans
*Neurodegenerative Diseases/drug therapy/enzymology/genetics/pathology
*Drug Discovery
*Protein Kinases/genetics/metabolism
*Protein Kinase Inhibitors/therapeutic use
Signal Transduction/drug effects/genetics
Phosphorylation
Animals

@article {pmid40328546,
year = {2025},
author = {Kleinerova, J and Tan, EL and Delaney, S and Smyth, M and Bede, P},
title = {Advances and research priorities in the respiratory management of ALS: Historical perspectives and new technologies.},
journal = {Revue neurologique},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neurol.2025.04.008},
pmid = {40328546},
issn = {0035-3787},
abstract = {Respiratory involvement has been identified as a cardinal feature of amyotrophic lateral sclerosis (ALS) since its earliest descriptions in the 19th century. Since these initial reports, considerable research has been undertaken to clarify the pathophysiology and progression rates associated with respiratory compromise and effective management strategies have been developed. Clinical trials routinely incorporate respiratory measures as study end points, non-invasive ventilation is now widely used in the home setting, cough-assist techniques are commonly used, advanced neurophysiology techniques and wearable technologies have been integrated into respiratory monitoring protocols, and palliative guidelines have been developed to effectively manage respiratory distress. Despite the widespread implementation of these interventions, epidemiology studies are inconsistent and some studies suggest that survival in ALS has not improved significantly with the introduction of these measures. The outcomes of diaphragmatic pacing trials have been disappointing, advanced neurophysiology techniques are not routinely utilised, spinal and brainstem imaging are not commonly undertaken and significant geographical differences exist in proceeding to tracheostomy. The worldwide COVID pandemic has given impetus for remote monitoring, connected devices, video-consultations, and timely vaccinations in ALS; lessons that are invaluable long after the pandemic. Respiratory monitoring and management in ALS is a swiftly evolving facet of ALS care with considerable quality of life benefits.},
}

@article {pmid40325332,
year = {2025},
author = {Liu, S and Feng, A and Li, Z},
title = {Neuron-Derived Extracellular Vesicles: Emerging Regulators in Central Nervous System Disease Progression.},
journal = {Molecular neurobiology},
volume = {},
number = {},
pages = {},
pmid = {40325332},
issn = {1559-1182},
abstract = {The diagnosis and exploration of central nervous system (CNS) diseases remain challenging due to the blood-brain barrier (BBB), complex signaling pathways, and heterogeneous clinical manifestations. Neurons, as the core functional units of the CNS, play a pivotal role in CNS disease progression. Extracellular vesicles (EVs), capable of crossing the BBB, facilitate intercellular and cell-extracellular matrix (ECM) communication, making neuron-derived extracellular vesicles (NDEVs) a focal point of research. Recent studies reveal that NDEVs, carrying various bioactive substances, can exert either pathogenic or protective effects in numerous CNS diseases. Additionally, NDEVs show significant potential as biomarkers for CNS diseases. This review summarizes the emerging roles of NDEVs in CNS diseases, including Alzheimer's disease, depression, traumatic brain injury, schizophrenia, ischemic stroke, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis. It aims to provide a novel perspective on developing therapeutic and diagnostic strategies for CNS diseases through the study of NDEVs.},
}

@article {pmid40022581,
year = {2025},
author = {Galvin, M and Heverin, M and Mac Domhnaill, É and Mcfarlane, R and Meldrum, D and Murray, D and Bolger, A and Connelly, J and Flynn, K and Fox, E and Gibbons, F and Hederman, L and Impey, S and O'Keefe, I and O'Meara, C and McKibben, D and Nicholson, M and Stephens, G and Van Dijk, J and Van Den Berg, L and Hardiman, O},
title = {Challenges and solutions to complex data governance issues in cross-national, cross-sectoral, multidisciplinary real world health research: a descriptive overview.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {26},
number = {sup1},
pages = {1-7},
doi = {10.1080/21678421.2024.2428927},
pmid = {40022581},
issn = {2167-9223},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/epidemiology ; *Biomedical Research ; *Precision Medicine ; Europe ; *Data Management ; },
abstract = {Real-world clinical data is generated during clinical engagements. The collection and further processing and mining of clinical information requires consents and navigation of necessary and important data governance processes. PRECISION ALS is an academic industry programme that collects, collates and analyses clinical and para-clinical data from patients with ALS across 10 European sites. The infrastructure of PRECISION ALS represents a complex interplay of the clinical, governance, and technical frameworks. Incorporation of infrastructural and operational measures enables sophisticated cross-national, cross-sectoral and cross disciplinary health research. PRECISION ALS has established a range of domain expertise, technologies, governance and clinical data management practices that can be applied throughout the life cycle of patient data from generation, collation, delivery and secure storage for advanced analytics. PRECISION ALS is designed to move the field of ALS research to a true Precision Medicine based approach toward new and more effective therapeutics.},
}

Humans
*Amyotrophic Lateral Sclerosis/therapy/epidemiology
*Biomedical Research
*Precision Medicine
Europe
*Data Management

@article {pmid39440770,
year = {2025},
author = {Allowitz, K and Taylor, J and Harames, K and Yoo, J and Baloch, O and Ramana, KV},
title = {Oxidative Stress-mediated Lipid Peroxidation-derived Lipid Aldehydes in the Pathophysiology of Neurodegenerative Diseases.},
journal = {Current neuropharmacology},
volume = {23},
number = {6},
pages = {671-685},
pmid = {39440770},
issn = {1875-6190},
mesh = {Humans ; *Oxidative Stress/physiology ; *Neurodegenerative Diseases/metabolism/physiopathology ; *Lipid Peroxidation/physiology ; *Aldehydes/metabolism ; Animals ; },
abstract = {Neurodegenerative diseases such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis cause damage and gradual loss of neurons affecting the central nervous system. Neurodegenerative diseases are most commonly seen in the ageing process. Ageing causes increased reactive oxygen species and decreased mitochondrial ATP generation, resulting in redox imbalance and oxidative stress. Oxidative stress-generated free radicals cause damage to membrane lipids containing polyunsaturated fatty acids, leading to the formation of toxic lipid aldehyde products such as 4- hydroxynonenal and malondialdehyde. Several studies have shown that lipid peroxidation-derived aldehyde products form adducts with cellular proteins, altering their structure and function. Thus, these lipid aldehydes could act as secondary signaling intermediates, modifying important metabolic pathways, and contributing to the pathophysiology of several human diseases, including neurodegenerative disorders. Additionally, they could serve as biomarkers for disease progression. This narrative review article discusses the biological and clinical significance of oxidative stress-mediated lipid peroxidation-derived lipid aldehydes in the pathophysiology of various neurodegenerative diseases.},
}

Humans
*Oxidative Stress/physiology
*Neurodegenerative Diseases/metabolism/physiopathology
*Lipid Peroxidation/physiology
*Aldehydes/metabolism
Animals

@article {pmid40320859,
year = {2025},
author = {Watanabe, S and Yamanaka, K},
title = {Mitochondria and Endoplasmic Reticulum Contact Site as a Regulator of Proteostatic Stress Responses in Neurodegenerative Diseases.},
journal = {BioEssays : news and reviews in molecular, cellular and developmental biology},
volume = {},
number = {},
pages = {e70016},
doi = {10.1002/bies.70016},
pmid = {40320859},
issn = {1521-1878},
support = {23K06826//Ministry of Education, Culture, Sports, Science and Technology, Japan/Japan Society for the Promotion of Science/ ; 19KK0214//Ministry of Education, Culture, Sports, Science and Technology, Japan/Japan Society for the Promotion of Science/ ; 22H00467//Ministry of Education, Culture, Sports, Science and Technology, Japan/Japan Society for the Promotion of Science/ ; JP22ek0109426//Japan Agency for Medical Research and Development/ ; JP24wm0425014//Japan Agency for Medical Research and Development/ ; JP24wm0625301//Japan Agency for Medical Research and Development/ ; //Takeda Science Foundation/ ; //Mochida Memorial Foundation for Medical and Pharmaceutical Research/ ; //Kowa Life Science Foundation/ ; //Novartis Foundation/ ; },
abstract = {Recent evidence indicates that the mitochondria-endoplasmic reticulum (ER) contact site is a novel microdomain essential for cellular homeostasis. Various proteins are accumulated at the mitochondria-associated membrane (MAM), an ER subcomponent closely associated with the mitochondria, contributing to Ca[2+] transfer to the mitochondria, lipid synthesis, mitochondrial fission/fusion, and autophagy. These functions are disrupted in the diseases, particularly in neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and Alzheimer's disease. In this review, we summarize the disruption of protein homeostasis in various neurodegenerative diseases, present recent works on the mechanisms of MAM aberration, including ours mainly focused on ALS, and then discuss challenges and prospects for future MAM-targeted therapies in neurodegenerative diseases.},
}

@article {pmid40320052,
year = {2025},
author = {Nadeem, A and Sharma, P and Gupta, P and Sandeep, P and Sharma, B and Sharma, N and Yadav, M and Dhiman, N},
title = {Exploring Neuregulin3: From physiology to pathology, a novel target for rational drug design.},
journal = {Biochemical pharmacology},
volume = {},
number = {},
pages = {116964},
doi = {10.1016/j.bcp.2025.116964},
pmid = {40320052},
issn = {1873-2968},
abstract = {Neuregulin 3 (NRG3) is an epidermal growth factor related protein that binds to and stimulates the Erb-B2 receptor tyrosine kinase 4 (ErbB4). NRG3 is a multifunctional protein with fifteen alternative splicing isoforms categorized into four classes. Numerous physiological processes, such as the formation of cortical plate, cortical patterning, synaptic development, neuronal proliferation, regulation of neurotransmission, control of impulsive behavior, mammary gland morphogenesis, spermatogonial proliferation and cardiac homeostasis are influenced by NRG3. Besides its physiological roles, NRG3 also modulates anxiogenic phenotypes. It is a susceptibility gene for schizophrenia, autism spectrum disorder and Hirschsprung's Disease. Furthermore, anxiety during nicotine withdrawal is dependent on NRG3-ErbB4 signaling. Research on a range of solid carcinomas, such as brain tumors, ovarian cancer, gastrointestinal cancer and breast cancer, has demonstrated NRG3 gene as a therapeutic target. NRG3 also has potential involvement in epilepsy, angular limb malformation in Rambouillet rams, amyotrophic lateral sclerosis and polythelia. Nevertheless, little is known about the molecular characteristics, activities specific to isoforms, and molecular mechanisms of NRG3. Examining its potential involvement in a range of physiological processes and pathological states is a unique area that needs in-depth study and may offer new mechanistic insights and comprehension of these elements. Thus, the purpose of this review is to shed light on the utility of NRG3 as a potential target in various health and disease conditions.},
}

@article {pmid40319325,
year = {2025},
author = {Mehdizadeh, S and Mamaghani, M and Hassanikia, S and Pilehvar, Y and Ertas, YN},
title = {Exosome-powered neuropharmaceutics: unlocking the blood-brain barrier for next-gen therapies.},
journal = {Journal of nanobiotechnology},
volume = {23},
number = {1},
pages = {329},
pmid = {40319325},
issn = {1477-3155},
mesh = {*Exosomes/metabolism/chemistry ; *Blood-Brain Barrier/metabolism/drug effects ; Humans ; Animals ; *Drug Delivery Systems/methods ; *Neuropharmacology/methods ; Drug Carriers/chemistry ; },
abstract = {BACKGROUND: The blood-brain barrier (BBB) presents a formidable challenge in neuropharmacology, limiting the delivery of therapeutic agents to the brain. Exosomes, nature's nanocarriers, have emerged as a promising solution due to their biocompatibility, low immunogenicity, and innate ability to traverse the BBB. A thorough examination of BBB anatomy and physiology reveals the complexities of neurological drug delivery and underscores the limitations of conventional methods.

MAIN BODY: This review explores the potential of exosome-powered neuropharmaceutics, highlighting their structural and functional properties, biogenesis, and mechanisms of release. Their intrinsic advantages in drug delivery, including enhanced stability and efficient cellular uptake, are discussed in detail. Exosomes naturally overcome BBB barriers through specific translocation mechanisms, making them a compelling vehicle for targeted brain therapies. Advances in engineering strategies, such as genetic and biochemical modifications, drug loading techniques, and specificity enhancement, further bolster their therapeutic potential. Exosome-based approaches hold immense promise for treating a spectrum of neurological disorders, including Alzheimer's, Parkinson's, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), brain tumors, stroke, and psychiatric conditions.

CONCLUSION: By leveraging their innate properties and engineering innovations, exosomes offer a versatile platform for precision neurotherapeutics. Despite their promise, challenges remain in clinical translation, including large-scale production, standardization, and regulatory considerations. Future research directions in exosome nanobiotechnology aim to refine these therapeutic strategies, unlocking new avenues for treating neurological diseases. This review underscores the transformative impact of exosome-based drug delivery, paving the way for next-generation therapies that can effectively penetrate the BBB and revolutionize neuropharmacology.},
}

*Exosomes/metabolism/chemistry
*Blood-Brain Barrier/metabolism/drug effects
Humans
Animals
*Drug Delivery Systems/methods
*Neuropharmacology/methods
Drug Carriers/chemistry

@article {pmid40314791,
year = {2025},
author = {Iuzzolino, VV and Scaravilli, A and Carignani, G and Senerchia, G and Pontillo, G and Dubbioso, R and Cocozza, S},
title = {Mapping motor and extra-motor gray and white matter changes in ALS: a comprehensive review of MRI insights.},
journal = {Neuroradiology},
volume = {},
number = {},
pages = {},
pmid = {40314791},
issn = {1432-1920},
abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease primarily affecting motor neurons, yet with substantial clinical variability. Furthermore, beyond motor symptoms, ALS patients also show non-motor features, reflecting its classification as a multi-system disorder. The identification of reliable biomarkers is a critical challenge for improving diagnosis, tracking disease progression, and predicting patient outcomes. This review explores macro- and microstructural alterations in ALS, focusing on gray matter (GM) and white matter (WM) as observed through Magnetic Resonance Imaging (MRI). This approach synthesizes not only the expected involvement of motor areas but also highlights emerging evidence that these changes extend to extra-motor areas, such as the frontal and temporal lobes, underscoring the complex pathophysiology of ALS. The review emphasizes the potential of MRI as a non-invasive tool to provide new biomarkers by assessing both GM and WM integrity, a key advancement in ALS research. Additionally, it addresses existing discrepancies in findings and stresses the need for standardized imaging protocols. It also highlights the role of multi-modal MRI approaches in deepening our understanding of ALS pathology, emphasizing the importance of combining structural and diffusion MRI techniques to offer more comprehensive insights into ALS progression, ultimately advancing the potential for personalized treatment strategies and improving patient outcomes.},
}

@article {pmid40309800,
year = {2025},
author = {Manai, AL and Caria, P and Noli, B and Contini, C and Manconi, B and Etzi, F and Cocco, C},
title = {VGF and Its Derived Peptides in Amyotrophic Lateral Sclerosis.},
journal = {Brain sciences},
volume = {15},
number = {4},
pages = {},
pmid = {40309800},
issn = {2076-3425},
abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by a progressive degeneration in the neurons of the frontal cortex, spinal cord, and brainstem, altering the correct release of neurotransmitters. The disease affects every muscle in the body and could cause death three to five years after symptoms first occur. There is currently no efficient treatment to stop the disease's progression. The lack of identification of potential therapeutic strategies is a consequence of the delayed diagnosis due to the absence of accurate ALS early biomarkers. Indeed, neurotransmitters altered in ALS are not measurable in body fluids at quantities that allow for testing, making their use as diagnostic tools a challenge. Contrarily, neuroproteins and neuropeptides are chemical messengers produced and released by neurons, and most of them have the potential to enter bodily fluids. To find out new possible ALS biomarkers, the research of neuropeptides and proteins is intensified using mass spectrometry and biochemical-based assays. Neuropeptides derived from the proVGF precursor protein act as signaling molecules within neurons. ProVGF and its derived peptides are expressed in the nervous and endocrine systems but are also widely distributed in body fluids such as blood, urine, and cerebrospinal fluid, making them viable options as disease biomarkers. To highlight the proVGF and its derived peptides' major roles as ALS diagnostic biomarkers, this review provides an overview of the VGF peptide alterations in spinal cord and body fluids and outlines the limitations of the reported investigations.},
}

@article {pmid40309789,
year = {2025},
author = {Khan, S and Kallis, L and Mee, H and El Hadwe, S and Barone, D and Hutchinson, P and Kolias, A},
title = {Invasive Brain-Computer Interface for Communication: A Scoping Review.},
journal = {Brain sciences},
volume = {15},
number = {4},
pages = {},
pmid = {40309789},
issn = {2076-3425},
abstract = {BACKGROUND: The rapid expansion of the brain-computer interface for patients with neurological deficits has garnered significant interest, and for patients, it provides an additional route where conventional rehabilitation has its limits. This has particularly been the case for patients who lose the ability to communicate. Circumventing neural injuries by recording from the intact cortex and subcortex has the potential to allow patients to communicate and restore self-expression. Discoveries over the last 10-15 years have been possible through advancements in technology, neuroscience, and computing. By examining studies involving intracranial brain-computer interfaces that aim to restore communication, we aimed to explore the advances made and explore where the technology is heading.

METHODS: For this scoping review, we systematically searched PubMed and OVID Embase. After processing the articles, the search yielded 41 articles that we included in this review.

RESULTS: The articles predominantly assessed patients who had either suffered from amyotrophic lateral sclerosis, cervical cord injury, or brainstem stroke, resulting in tetraplegia and, in some cases, difficulty speaking. Of the intracranial implants, ten had ALS, six had brainstem stroke, and thirteen had a spinal cord injury. Stereoelectroencephalography was also used, but the results, whilst promising, are still in their infancy. Studies involving patients who were moving cursors on a screen could improve the speed of movement by optimising the interface and utilising better decoding methods. In recent years, intracortical devices have been successfully used for accurate speech-to-text and speech-to-audio decoding in patients who are unable to speak.

CONCLUSIONS: Here, we summarise the progress made by BCIs used for communication. Speech decoding directly from the cortex can provide a novel therapeutic method to restore full, embodied communication to patients suffering from tetraplegia who otherwise cannot communicate.},
}

@article {pmid40309514,
year = {2025},
author = {Li, V and Huang, Y},
title = {Oligonucleotide therapeutics for neurodegenerative diseases.},
journal = {NeuroImmune pharmacology and therapeutics},
volume = {4},
number = {1},
pages = {1-11},
pmid = {40309514},
issn = {2750-6665},
abstract = {Recently there has been a surge in interest involving the application of oligonucleotides, including small interfering RNA (siRNA) and antisense oligonucleotides (ASOs), for the treatment of chronic diseases that have few available therapeutic options. This emerging class of drugs primarily operates by selectively suppressing target genes through antisense and/or RNA interference mechanisms. While various commercial medications exist for delivering oligonucleotides to the hepatic tissue, achieving effective delivery to extra hepatic tissues remains a formidable challenge. Here, we review recent advances in oligonucleotide technologies, including nanoparticle delivery, local administration, and 2'-O-hexadecyl (C16)-conjugation that work to extend the applicability of siRNAs and ASOs to nerve tissues. We discuss critical factors pivotal for the successful clinical translations of these modified or engineered oligonucleotides in the context of treating neurodegenerative diseases such as Alzheimer's disease and amyotrophic lateral sclerosis.},
}

@article {pmid40305176,
year = {2025},
author = {Erichsen, PA and Henriksen, EE and Nielsen, JE and Ejlerskov, P and Simonsen, AH and Toft, A},
title = {Immunological Fluid Biomarkers in Frontotemporal Dementia: A Systematic Review.},
journal = {Biomolecules},
volume = {15},
number = {4},
pages = {},
pmid = {40305176},
issn = {2218-273X},
support = {0084960//Novo Nordisk Foundation/ ; R450-2023-989//Lundbeck Foundation/ ; },
mesh = {Humans ; *Frontotemporal Dementia/immunology/blood/cerebrospinal fluid ; *Biomarkers/cerebrospinal fluid/blood ; Alzheimer Disease/immunology/blood/cerebrospinal fluid ; Amyotrophic Lateral Sclerosis/blood/immunology/cerebrospinal fluid ; Chitinase-3-Like Protein 1/cerebrospinal fluid/blood ; Glial Fibrillary Acidic Protein/cerebrospinal fluid/blood ; Chemokine CCL2/cerebrospinal fluid/blood ; },
abstract = {Dysregulated immune activation plays a key role in the pathogenesis of neurodegenerative diseases, including frontotemporal dementia (FTD). This study reviews immunological biomarkers associated with FTD and its subtypes. A systematic search of PubMed and Web of Science was conducted for studies published before 1 January 2025, focusing on immunological biomarkers in CSF or blood from FTD patients with comparisons to healthy or neurological controls. A total of 124 studies were included, involving 6686 FTD patients and 202 immune biomarkers. Key findings include elevated levels of GFAP and MCP1/CCL2 in both CSF and blood and consistently increased CHIT1 and YKL-40 in CSF. Complement proteins from the classical activation pathway emerged as promising targets. Distinct immune markers were found to differentiate FTD from Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS), with GFAP, SPARC, and SPP1 varying between FTD and AD and IL-15, HERV-K, NOD2, and CHIT1 differing between FTD and ALS. A few markers, such as Galectin-3 and PGRN, distinguished FTD subtypes. Enrichment analysis highlighted IL-10 signaling and immune cell chemotaxis as potential pathways for further exploration. This study provides an overview of immunological biomarkers in FTD, emphasizing those most relevant for future research on immune dysregulation in FTD pathogenesis.},
}

Humans
*Frontotemporal Dementia/immunology/blood/cerebrospinal fluid
*Biomarkers/cerebrospinal fluid/blood
Alzheimer Disease/immunology/blood/cerebrospinal fluid
Amyotrophic Lateral Sclerosis/blood/immunology/cerebrospinal fluid
Chitinase-3-Like Protein 1/cerebrospinal fluid/blood
Glial Fibrillary Acidic Protein/cerebrospinal fluid/blood
Chemokine CCL2/cerebrospinal fluid/blood

@article {pmid40302786,
year = {2025},
author = {Vijayaraghavan, M and Murali, SP and Thakur, G and Li, XJ},
title = {Role of glial cells in motor neuron degeneration in hereditary spastic paraplegias.},
journal = {Frontiers in cellular neuroscience},
volume = {19},
number = {},
pages = {1553658},
pmid = {40302786},
issn = {1662-5102},
abstract = {This review provides a comprehensive overview of hereditary spastic paraplegias (HSPs) and summarizes the recent progress on the role of glial cells in the pathogenesis of HSPs. HSPs are a heterogeneous group of neurogenetic diseases characterized by axonal degeneration of cortical motor neurons, leading to muscle weakness and atrophy. Though the contribution of glial cells, especially astrocytes, to the progression of other motor neuron diseases like amyotrophic lateral sclerosis (ALS) is well documented, the role of glial cells and the interaction between neurons and astrocytes in HSP remained unknown until recently. Using human pluripotent stem cell-based models of HSPs, a study reported impaired lipid metabolisms and reduced size of lipid droplets in HSP astrocytes. Moreover, targeting lipid dysfunction in astrocytes rescues axonal degeneration of HSP cortical neurons, demonstrating a non-cell-autonomous mechanism in axonal deficits of HSP neurons. In addition to astrocytes, recent studies revealed dysfunctions in HSP patient pluripotent stem cell-derived microglial cells. Increased microgliosis and pro-inflammation factors were also observed in HSP patients' samples, pointing to an exciting role of innate immunity and microglia in HSP. Building upon these recent studies, further investigation of the detailed molecular mechanism and the interplay between glial cell dysfunction and neuronal degeneration in HSP by combining human stem cell models, animal models, and patient samples will open avenues for identifying new therapeutic targets and strategies for HSP.},
}

@article {pmid40301152,
year = {2025},
author = {Armas, JMB and Taoro-González, L and Fisher, EMC and Acevedo-Arozena, A},
title = {Challenges of modelling TDP-43 pathology in mice.},
journal = {Mammalian genome : official journal of the International Mammalian Genome Society},
volume = {},
number = {},
pages = {},
pmid = {40301152},
issn = {1432-1777},
abstract = {TDP-43 is a normally nuclear RNA binding protein that under pathological conditions may be excluded from the nucleus and deposited in the cytoplasm in the form of insoluble polyubiquitinated and polyphosphorylated inclusions. This nuclear exclusion coupled with cytoplasmic accumulation is called TDP-43 pathology and contributes to a range of disorders collectively known as TDP-43 proteinopathies. These include the great majority of amyotrophic lateral sclerosis (ALS) cases, all limbic-predominant age-related TDP-43 encephalopathy (LATE), as well as up to 50% of frontotemporal lobar degeneration (FTLD) and Alzheimer's disease (AD) cases. Thus, TDP-43 pathology is a common feature underlying a wide range of neurodegenerative conditions. However, modelling it has proven to be challenging, particularly generating models with concomitant TDP-43 loss of nuclear function and cytoplasmic inclusions. Here, focussing exclusively on mice, we discuss TDP-43 genetic models in terms of the presence of TDP-43 pathology, and we consider other models with TDP-43 pathology due to mutations in disparate genes. We also consider manipulations aimed at producing TDP-43 pathology, and we look at potential strategies to develop new, much needed models to address the many outstanding questions regarding how and why TDP-43 protein leaves the nucleus and accumulates in the cytoplasm, causing downstream dysfunction and devastating disease.},
}

@article {pmid39779313,
year = {2025},
author = {Xiao, Y and Tan, Y and Li, C and Wei, Q and Jiang, Q and Wang, S and Yang, T and Lin, J and Zhang, L and Shang, H},
title = {Genetic and clinical analysis of OPTN in amyotrophic lateral sclerosis.},
journal = {Journal of medical genetics},
volume = {62},
number = {4},
pages = {242-248},
doi = {10.1136/jmg-2024-109978},
pmid = {39779313},
issn = {1468-6244},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; *Membrane Transport Proteins/genetics ; *Cell Cycle Proteins/genetics ; *Transcription Factor TFIIIA/genetics ; Female ; Male ; Middle Aged ; Genetic Association Studies ; Phenotype ; Genotype ; *Genetic Predisposition to Disease ; Aged ; Adult ; Mutation ; Asian People/genetics ; },
abstract = {BACKGROUND: Considerable heterogeneity in genotypes and phenotypes has been observed among patients with amyotrophic lateral sclerosis (ALS) harbouring optineurin gene (OPTN) mutations, as reported in prior studies. The study aimed to elucidate the correlation between OPTN genotypes and phenotypes.

METHODS: OPTN gene variants were screened within a substantial Chinese cohort of patients with ALS, encompassing LoF and rare missense variants. Additionally, a systematic literature review was conducted to compile the spectrum of OPTN mutations and explore the relationship between the genotype and phenotype of patients with ALS with OPTN.

RESULTS: A total of 33 unrelated patients with ALS with 24 rare OPTN variants, including 17 novel variants, were identified in 2279 patients with ALS. Among 24 variants in our cohort and 106 variants in previous studies, only 33.3% and 35.8% were pathogenic/likely pathogenic variants. Moreover, the frequency of OPTN variants in the Asian ALS population was higher (1.08%) than that of the Caucasian population (0.55%). For the phenotype of patients with ALS carrying OPTN variants, we found that patients with pathogenic/likely pathogenic variants had the highest baseline progression rate and the shortest survival time among groups in our cohort.

CONCLUSION: Our study contributed to a broader understanding of the genotype and phenotype spectrum of patients with ALS carrying OPTN variants. Further investigations are warranted to definitively establish the genotype-phenotype associations.},
}

Humans
*Amyotrophic Lateral Sclerosis/genetics/pathology
*Membrane Transport Proteins/genetics
*Cell Cycle Proteins/genetics
*Transcription Factor TFIIIA/genetics
Female
Male
Middle Aged
Genetic Association Studies
Phenotype
Genotype
*Genetic Predisposition to Disease
Aged
Adult
Mutation
Asian People/genetics

@article {pmid40300682,
year = {2025},
author = {Li, Z and Xing, J},
title = {Role of sirtuins in cerebral ischemia-reperfusion injury: Mechanisms and therapeutic potential.},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {143591},
doi = {10.1016/j.ijbiomac.2025.143591},
pmid = {40300682},
issn = {1879-0003},
abstract = {The high incidence and mortality rate of cardiac arrest (CA) establishes it as a critical clinical challenge in emergency medicine globally. Despite continuous advances in advanced life support (ALS) technology, the prognosis for patients experiencing cardiac arrest remains poor, with cerebral ischemia and reperfusion injury (CIRI) being a significant determinant of adverse neurological outcomes and increased mortality. Sirtuins (SIRTs) are a class of highly evolutionarily conserved NAD[+]-dependent histone deacylenzymes capable of regulating the expression of various cytoprotective genes to play a neuroprotective role in CIRI. SIRTs mainly regulate the levels of downstream proteins such as PGC 1-α, Nrf 2, NLRP 3, FoxOs, and PINK 1 to inhibit inflammatory response, attenuate oxidative stress, improve mitochondrial dysfunction, promote angiogenesis, and inhibit apoptosis while reducing CIRI. Natural active ingredients are widely used in regulating the protein level of SIRTs in the body because of their multi-components, multi-pathway, multi-target, and minimal toxic side effects. However, these naturally active ingredients still face many challenges related to drug targeting, pharmacokinetic properties, and drug delivery. The emergence and vigorous development of new drug delivery systems, such as nanoparticles, micromilk, and exosomes, provide strong support for solving the above problems. In the context of the rapid development of molecular biology technology, non-coding RNA (NcRNA), represented by miRNA and LncRNA, offers great potential for achieving gene-level precision medicine. In the context of multidisciplinary integration, combining SIRTs proteins with biotechnology, omics technologies, artificial intelligence, and material science will strongly promote the deepening of their basic research and expand their clinical application. This review describes the major signaling pathways of targeting SIRTs to mitigate CIRI, as well as the current research status of Chinese and Western medicine and medical means for the intervention level of SIRTs. Meanwhile, the challenges and possible solutions in the clinical application of targeted drugs are summarized. In the context of medical and industrial crossover, the development direction of SIRTs in the future is discussed to provide valuable reference for basic medical researchers and clinicians to improve the clinical diagnosis and treatment effects of CIRI.},
}

@article {pmid40300213,
year = {2025},
author = {Sun, Y and Vermulst, M},
title = {The hidden costs of imperfection: transcription errors in protein aggregation diseases.},
journal = {Current opinion in genetics & development},
volume = {93},
number = {},
pages = {102350},
doi = {10.1016/j.gde.2025.102350},
pmid = {40300213},
issn = {1879-0380},
abstract = {At first glance, biological systems appear to operate with remarkable precision and order. Yet, closer examination reveals that this perfection is an illusion, biological processes are inherently prone to errors. Here, we describe recent evidence that indicates that errors that occur during transcription play an important role in neurological diseases. These errors, though transient, can have lasting consequences when they generate mutant proteins with amyloid or prion-like properties. Such proteins can seed aggregation cascades, converting wild-type counterparts into misfolded conformations, ultimately leading to toxic deposits seen in diseases like Alzheimer's and amyotrophic lateral sclerosis. These observations help to paint a fuller picture of the origins of neurodegenerative diseases in aging humans and suggest a unified mechanism by which they may arise.},
}

@article {pmid40299664,
year = {2025},
author = {Nogueira-Machado, JA and Rocha-Silva, F and Gomes, NA},
title = {The Role of mTOR in Amyotrophic Lateral Sclerosis.},
journal = {Biomedicines},
volume = {13},
number = {4},
pages = {},
doi = {10.3390/biomedicines13040952},
pmid = {40299664},
issn = {2227-9059},
abstract = {Background: Amyotrophic lateral sclerosis (ALS) is a rare, progressive, and incurable disease characterized by muscle weakness and paralysis. Recent studies have explored a possible link between ALS pathophysiology and mTOR signaling. Recent reports have linked the accumulation of protein aggregates, dysfunctional mitochondria, and homeostasis to the development of ALS. mTOR plays a pivotal role in controlling autophagy and affecting energy metabolism, in addition to supporting neuronal growth, plasticity, and the balance between apoptosis and autophagy, all of which are important for homeostasis. Aim: This mini-review approaches the regulatory roles of mTOR signaling pathways, their interaction with other metabolic pathways, and their potential to modulate ALS progression. Significance: It discusses how these metabolic signaling pathways affect the neuromuscular junction, producing symptoms of muscle weakness and atrophy similar to those seen in patients with ALS. The discussion includes the concepts of neurocentric and peripheral and the possible connection between mTOR and neuromuscular dysfunction in ALS. Conclusions: It highlights the therapeutic potential of mTOR signaling and interconnections with other metabolic routes, making it a promising biomarker and therapeutic target for ALS.},
}

@article {pmid40299512,
year = {2025},
author = {Eslami, M and Adampour, Z and Fadaee Dowlat, B and Yaghmayee, S and Motallebi Tabaei, F and Oksenych, V and Naderian, R},
title = {A Novel Frontier in Gut-Brain Axis Research: The Transplantation of Fecal Microbiota in Neurodegenerative Disorders.},
journal = {Biomedicines},
volume = {13},
number = {4},
pages = {},
doi = {10.3390/biomedicines13040915},
pmid = {40299512},
issn = {2227-9059},
abstract = {The gut-brain axis (GBA) represents a sophisticated bidirectional communication system connecting the central nervous system (CNS) and the gastrointestinal (GI) tract. This interplay occurs primarily through neuronal, immune, and metabolic pathways. Dysbiosis in gut microbiota has been associated with multiple neurodegenerative diseases, such as Parkinson's disease (PD), Alzheimer's disease (AD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS). In recent years, fecal microbiota transplantation (FMT) has gained attention as an innovative therapeutic approach, aiming to restore microbial balance in the gut while influencing neuroinflammatory and neurodegenerative pathways. This review explores the mechanisms by which FMT impacts the gut-brain axis. Key areas of focus include its ability to reduce neuroinflammation, strengthen gut barrier integrity, regulate neurotransmitter production, and reinstate microbial diversity. Both preclinical and clinical studies indicate that FMT can alleviate motor and cognitive deficits in PD and AD, lower neuroinflammatory markers in MS, and enhance respiratory and neuromuscular functions in ALS. Despite these findings, several challenges remain, including donor selection complexities, uncertainties about long-term safety, and inconsistencies in clinical outcomes. Innovations such as synthetic microbial communities, engineered probiotics, and AI-driven analysis of the microbiome hold the potential to improve the precision and effectiveness of FMT in managing neurodegenerative conditions. Although FMT presents considerable promise as a therapeutic development, its widespread application for neurodegenerative diseases requires thorough validation through well-designed, large-scale clinical trials. It is essential to establish standardized protocols, refine donor selection processes, and deepen our understanding of the molecular mechanisms behind its efficacy.},
}

@article {pmid40299102,
year = {2025},
author = {Zhang, G and Huang, S and Wei, M and Wu, Y and Wang, J},
title = {Excitatory Amino Acid Transporters as Therapeutic Targets in the Treatment of Neurological Disorders: Their Roles and Therapeutic Prospects.},
journal = {Neurochemical research},
volume = {50},
number = {3},
pages = {155},
pmid = {40299102},
issn = {1573-6903},
support = {2023JJB140089//Guangxi Youth Science Foundation Project/ ; 82201694//the National Natural Scientific Foundation of China/ ; 2022AC21033//Guangxi Science and technology base and talent project/ ; 2022KY0349//Guangxi university young and middle-aged teachers' basic ability improvement project/ ; },
mesh = {Humans ; Animals ; *Nervous System Diseases/metabolism/drug therapy ; *Glutamate Plasma Membrane Transport Proteins/metabolism ; Glutamic Acid/metabolism ; },
abstract = {Excitatory amino acid transporters (EAATs) are pivotal regulators of glutamate homeostasis in the central nervous system and orchestrate synaptic glutamate clearance through transmembrane transport and the glutamine‒glutamate cycle. The five EAAT subtypes (GLAST/EAAT1, GLT-1/EAAT2, EAAC1/EAAT3, EAAT4, and EAAT5) exhibit spatiotemporal-specific expression patterns in neurons and glial cells, and their dysfunction is implicated in diverse neurological pathologies, including epilepsy, amyotrophic lateral sclerosis (ALS), schizophrenia, depression, and retinal degeneration. Mechanistic studies revealed that astrocytic GLT-1 deficiency disrupts glutamate clearance in ALS motor neurons, whereas GLAST genetic variants are linked to both epilepsy susceptibility and glaucomatous retinal ganglion cell degeneration. Three major challenges persist in ongoing research: ① subtype-specific regulatory mechanisms remain unclear; ② compensatory functions of transporters vary significantly across disease models; and ③ clinical translation lacks standardized evaluation criteria. The interaction mechanisms and dynamic roles of EAATs in neurological disorders were systematically investigated in this study, and an integrated approach combining single-cell profiling, stem cell-based disease modeling, and drug screening platforms was proposed. These findings lay the groundwork for novel therapeutic strategies targeting glutamate homeostasis.},
}

Humans
Animals
*Nervous System Diseases/metabolism/drug therapy
*Glutamate Plasma Membrane Transport Proteins/metabolism
Glutamic Acid/metabolism

@article {pmid40299101,
year = {2025},
author = {Sarkar, S and Porel, P and Kosey, S and Aran, KR},
title = {Unraveling the role of CGRP in neurological diseases: a comprehensive exploration to pathological mechanisms and therapeutic implications.},
journal = {Molecular biology reports},
volume = {52},
number = {1},
pages = {436},
pmid = {40299101},
issn = {1573-4978},
mesh = {Humans ; *Calcitonin Gene-Related Peptide/metabolism/genetics ; Animals ; Neuroprotective Agents/pharmacology/therapeutic use/metabolism ; *Neurodegenerative Diseases/metabolism/drug therapy/pathology ; *Nervous System Diseases/metabolism ; Signal Transduction ; Receptors, Calcitonin Gene-Related Peptide/metabolism ; Oxidative Stress ; },
abstract = {Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Multiple sclerosis (MS), Amyotrophic lateral sclerosis (ALS), and Spinal muscular atrophy (SMA) are neurodegenerative diseases (NDDs) characterized by progressive neuronal degeneration. Recent studies provide compelling information regarding the contribution of Calcitonin Gene-Related Peptide (CGRP), a potent neuropeptide, in regulating neuroinflammation, vasodilation, and neuronal survival in these disorders. This review systematically delves into the multidimensional aspects of CGRP as both a neuroprotective agent and a neurotoxic factor in NDDs. The neuroprotective effects of CGRP include suppression of inflammation, regulation of intracellular signaling pathways, and promotion of neuronal growth and survival. However, under pathological conditions, its overexpression or dysregulation is associated with oxidative stress, excitotoxicity, and neuronal death. The therapeutic use of CGRP and its receptor antagonists in migraine provides substantial evidence for CGRP's therapeutic potential, which can be further explored for the management of NDDs. However, since the bidirectional nature of CGRP effects is evident, it is crucial to gain an accurate insight into its mechanisms to target only the neuropeptide's beneficial effects while completely avoiding the undesired consequences. Further studies should focus on understanding the context-dependent activity of CGRP in the hope of designing targeted therapy for NDDs, which could gradually transform the current pharmacological management of NDDs.},
}

Humans
*Calcitonin Gene-Related Peptide/metabolism/genetics
Animals
Neuroprotective Agents/pharmacology/therapeutic use/metabolism
*Neurodegenerative Diseases/metabolism/drug therapy/pathology
*Nervous System Diseases/metabolism
Signal Transduction
Receptors, Calcitonin Gene-Related Peptide/metabolism
Oxidative Stress

@article {pmid40298821,
year = {2025},
author = {Bortolotti, M and Polito, L and Battelli, MG and Bolognesi, A},
title = {Xanthine Oxidoreductase: A Double-Edged Sword in Neurological Diseases.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {14},
number = {4},
pages = {},
doi = {10.3390/antiox14040483},
pmid = {40298821},
issn = {2076-3921},
abstract = {Non-communicable neurological disorders are the second leading cause of death, and their burden continues to increase as the world population grows and ages. Oxidative stress and inflammation are crucially implicated in the triggering and progression of multiple sclerosis, Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease, and even stroke. In this narrative review, we examine the role of xanthine oxidoreductase (XOR) activities and products in all the above-cited neurological diseases. The redox imbalance responsible for oxidative stress could arise from excess reactive oxygen and nitrogen species resulting from the activities of XOR, as well as from the deficiency of its main product, uric acid (UA), which is the pivotal antioxidant system in the blood. In fact, with the exception of stroke, serum UA levels are inversely related to the onset and progression of these neurological disorders. The inverse correlation observed between the level of uricemia and the presence of neurological diseases suggests a neuroprotective role for UA. Oxidative stress and inflammation are also caused by ischemia and reperfusion, a condition in which XOR action has been recognized as a contributing factor to tissue damage. The findings reported in this review could be useful for addressing clinical decision-making and treatment optimization.},
}

@article {pmid40290120,
year = {2025},
author = {Hong, Y and Song, Y and Wang, W and Shi, J and Chen, X},
title = {Mitochondrial DNA editing: Key to the treatment of neurodegenerative diseases.},
journal = {Genes & diseases},
volume = {12},
number = {4},
pages = {101437},
pmid = {40290120},
issn = {2352-3042},
abstract = {Neuronal death is associated with mitochondrial dysfunction caused by mutations in mitochondrial DNA. Mitochondrial DNA becomes damaged when processes such as replication, repair, and nucleotide synthesis are compromised. This extensive accumulation of damaged mitochondrial DNA subsequently disrupts the normal function of mitochondria, leading to aging, degeneration, or even death of neurons. Mitochondrial dysfunction stands as a pivotal factor in the development of neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis. Recognizing the intricate nature of their pathogenesis, there is an urgent need for more effective therapeutic interventions. In recent years, mitochondrial DNA editing tools such as zinc finger nucleases, double-stranded DNA deaminase toxin A-derived cytosine base editors, and transcription activator-like effector ligand deaminases have emerged. Their emergence will revolutionize the research and treatment of mitochondrial diseases. In this review, we summarize the advancements in mitochondrial base editing technology and anticipate its utilization in neurodegenerative diseases, offering insights that may inform preventive strategies and therapeutic interventions for disease phenotypes.},
}

@article {pmid40288591,
year = {2025},
author = {Servi, R and Akkoç, RF and Aksu, F and Servi, S},
title = {Therapeutic Potential of Enzymes, Neurosteroids, and Synthetic Steroids in Neurodegenerative Disorders: A Critical Review.},
journal = {The Journal of steroid biochemistry and molecular biology},
volume = {},
number = {},
pages = {106766},
doi = {10.1016/j.jsbmb.2025.106766},
pmid = {40288591},
issn = {1879-1220},
abstract = {Neurodegenerative disorders present a significant challenge to healthcare systems, mainly due to the limited availability of effective treatment options to halt or reverse disease progression. Endogenous steroids synthesized in the central nervous system, such as pregnenolone (PREG), dehydroepiandrosterone (DHEA), progesterone (PROG), and allopregnanolone (ALLO), have been identified as potential therapeutic agents for neurodegenerative diseases. Neurosteroids such as ALLO, DHEA, and PROG, as well as their synthetic analogs like Ganaxolene, Fluasterone, and Olexoxime, offer promising effects for conditions such as Alzheimer's disease (AD) and depression. Moreover, Brexanolone and Ganaxolone are synthetic steroids approved for the treatment of postpartum depression and epilepsy, respectively. Neurosteroids such as ALLO are crucial in modulating GABAergic neurotransmission and reducing neuroinflammation. These compounds enhance the activity of GABA-A receptors, leading to increased inhibitory signaling in the brain, which can help regulate mood, cognition, and neuroprotection. Small clinical trials and observational studies indicate that ALLO may have cognitive benefits, but no large-scale, definitive meta-analysis confirms a 20% improvement in AD patients. Mitochondrial dysfunction plays a vital role in the pathogenesis of numerous neurological diseases due to the high-energy demand and sensitivity of neurons to oxidative stress. Reduced mitochondrial function leads to amyloid-beta plaques and tau tangles accumulation in AD. In Parkinson's disease (PD), mitochondrial dysfunction resulting from the PINK1 or Parkin genes leads to energy deficiencies and the accumulation of toxic byproducts. Mutations in genes such as SOD1, C9orf72, and TDP-43 have been associated with mitochondrial dysfunction in amyotrophic lateral sclerosis (ALS). Moreover, studies on these neurodegenerative diseases suggest that inflammation is not merely a consequence of neurodegeneration but is also an essential factor in this process. Many neurological disorders involve multifaceted interactions between genetics, the environment, and immune responses, making it difficult to pinpoint their exact causes. Future research aims to overcome these hurdles through genetic advances, regenerative medicine, and personalized therapies. Cutting-edge technologies such as artificial intelligence and high-throughput screening are expected to accelerate drug discovery and improve diagnostic accuracy. Increasing collaboration between interdisciplinary fields such as bioinformatics, neuroscience, and immunology will lead to innovative treatment strategies. This comprehensive review discusses the therapeutic effects of enzymes, neurosteroids, and synthetic steroids in different neurodegenerative diseases, particularly AD, PD, ALS, and MS. Potential challenges in the therapeutic use of neurosteroids, such as the limited bioavailability and off-target effects of synthetic steroids, are also discussed, and an up-to-date and comprehensive review of the impact of these steroids on neurodegenerative disorders is presented.},
}

@article {pmid40287045,
year = {2025},
author = {Dudzisz, K and Wandzik, I},
title = {Antisense Oligonucleotides: A Promising Advancement in Neurodegenerative Disease Treatment.},
journal = {European journal of pharmacology},
volume = {},
number = {},
pages = {177644},
doi = {10.1016/j.ejphar.2025.177644},
pmid = {40287045},
issn = {1879-0712},
abstract = {Antisense oligonucleotides (ASOs) are a class of therapeutics designed to modulate gene expression and have shown promise in the treatment of various neurodegenerative diseases. As of March 2025, four ASO-based therapies have received approval for the treatment of neurodegenerative diseases, including spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS), and hereditary transthyretin amyloidosis (ATTR). These approvals underscore the therapeutic potential of ASOs as effective treatments for neurodegenerative diseases by addressing specific genetic abnormalities. This is best demonstrated by clinical studies in more than a dozen ASOs, which could pave the way for the development of new therapeutics soon. Moreover, the ongoing extended clinical studies, which target presymptomatic carriers, have significant potential to cure familial ALS based on the SOD1 gene mutation. This review provides an update on clinical trials, highlighting promising results and the challenges encountered.},
}

@article {pmid40284554,
year = {2025},
author = {Tamai, R and Kiyoura, Y},
title = {Candida Infections: The Role of Saliva in Oral Health-A Narrative Review.},
journal = {Microorganisms},
volume = {13},
number = {4},
pages = {},
pmid = {40284554},
issn = {2076-2607},
support = {21K10233, 23K09511//KAKEN/ ; },
abstract = {Candida species, particularly Candida albicans, are causative agents of oral infections to which immunocompromised patients are especially susceptible. Reduced saliva flow (xerostomia) can lead to Candida overgrowth, as saliva contains antibacterial components such as histatins and β-defensins that inhibit fungal growth and adhesion to the oral mucosa. Candida adheres to host tissues, forms biofilms, and secretes enzymes required for tissue invasion and immune evasion. Secretory asparaginyl proteinases (Saps) and candidalysin, a cytolytic peptide toxin, are vital to Candida virulence, and agglutinin-like sequence (Als) proteins are crucial for adhesion, invasion, and biofilm formation. C. albicans is a risk factor for dental caries and may increase periodontal disease virulence when it coexists with Porphyromonas gingivalis. Candida infections have been suggested to heighten the risk of oral cancer based on a relationship between Candida species and oral squamous cell carcinoma (OSCC) or oral potentially malignant disorder (OPMD). Meanwhile, β-glucan in the Candida cell wall has antitumor effects. In addition, Candida biofilms protect viruses such as herpesviruses and coxsackieviruses. Understanding the intricate interactions between Candida species, host immune responses, and coexisting microbial communities is essential for developing preventive and therapeutic strategies against oral Candida infections, particularly in immunocompromised individuals.},
}

@article {pmid40283578,
year = {2025},
author = {Mantle, D and Hargreaves, I},
title = {Coenzyme Q10 and the Blood-Brain Barrier: An Overview.},
journal = {Journal of clinical medicine},
volume = {14},
number = {8},
pages = {},
doi = {10.3390/jcm14082748},
pmid = {40283578},
issn = {2077-0383},
abstract = {Mitochondrial dysfunction is a common factor known to be involved in the pathogenesis of a number of neurological disorders, including Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis. Given the importance of coenzyme Q10 (CoQ10) in promoting normal mitochondrial function, and the deficiency of CoQ10 reported in such neurological disorders, there is a rationale for investigating the potential therapeutic role of supplementary CoQ10. However, while there is evidence for the efficacy of CoQ10 supplementation in animal models of the above disorders, randomised controlled clinical trials supplementing CoQ10 in PD, AD, or ALS have had disappointing outcomes. This in turn may be a reflection of the current uncertainty as to whether CoQ10 can access the blood-brain barrier in human subjects. In an attempt to further elucidate the disparity in outcomes of such preclinical and clinical studies, in this article we have reviewed evidence from the peer-reviewed literature to establish the ability of CoQ10 to access the brain via the BBB.},
}

@article {pmid40283201,
year = {2025},
author = {González-Sánchez, M and Ramírez-Expósito, MJ and Martínez-Martos, JM},
title = {Pathophysiology, Clinical Heterogeneity, and Therapeutic Advances in Amyotrophic Lateral Sclerosis: A Comprehensive Review of Molecular Mechanisms, Diagnostic Challenges, and Multidisciplinary Management Strategies.},
journal = {Life (Basel, Switzerland)},
volume = {15},
number = {4},
pages = {},
doi = {10.3390/life15040647},
pmid = {40283201},
issn = {2075-1729},
abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by the progressive degeneration of upper and lower motor neurons, leading to muscle atrophy, paralysis, and respiratory failure. This comprehensive review synthesizes the current knowledge on ALS pathophysiology, clinical heterogeneity, diagnostic frameworks, and evolving therapeutic strategies. Mechanistically, ALS arises from complex interactions between genetic mutations (e.g., in C9orf72, SOD1, TARDBP (TDP-43), and FUS) and dysregulated cellular pathways, including impaired RNA metabolism, protein misfolding, nucleocytoplasmic transport defects, and prion-like propagation of toxic aggregates. Phenotypic heterogeneity, manifesting as bulbar-, spinal-, or respiratory-onset variants, complicates its early diagnosis, which thus necessitates the rigorous application of the revised El Escorial criteria and emerging biomarkers such as neurofilament light chain. Clinically, ALS intersects with frontotemporal dementia (FTD) in up to 50% of the cases, driven by shared TDP-43 pathology and C9orf72 hexanucleotide expansions. Epidemiological studies have revealed a lifetime risk of 1:350, with male predominance (1.5:1) and peak onset between 50 and 70 years. Disease progression varies widely, with a median survival of 2-4 years post-diagnosis, underscoring the urgency for early intervention. Approved therapies, including riluzole (glutamate modulation), edaravone (antioxidant), and tofersen (antisense oligonucleotide), offer modest survival benefits, while dextromethorphan/quinidine alleviates the pseudobulbar affect. Non-pharmacological treatment advances, such as non-invasive ventilation (NIV), prolong survival by 13 months and improve quality of life, particularly in bulb-involved patients. Multidisciplinary care-integrating physical therapy, respiratory support, nutritional management, and cognitive assessments-is critical to addressing motor and non-motor symptoms (e.g., dysphagia, spasticity, sleep disturbances). Emerging therapies show promise in preclinical models. However, challenges persist in translating genetic insights into universally effective treatments. Ethical considerations, including euthanasia and end-of-life decision-making, further highlight the need for patient-centered communication and palliative strategies.},
}

@article {pmid40282367,
year = {2025},
author = {Watanabe, Y and Nakagawa, T and Nakagawa, M and Nakayama, K},
title = {The Molecular Intersection of NEK1, C21ORF2, Cyclin F, and VCP in ALS Pathogenesis.},
journal = {Genes},
volume = {16},
number = {4},
pages = {},
doi = {10.3390/genes16040407},
pmid = {40282367},
issn = {2073-4425},
support = {23K06367//Japan Society for the Promotion of Science/ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *NIMA-Related Kinase 1/genetics/metabolism ; *Valosin Containing Protein/genetics/metabolism ; *Cyclins/genetics/metabolism ; DNA-Binding Proteins/genetics/metabolism ; Animals ; DNA Damage ; Mutation ; DNA Repair ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterized by the progressive degeneration of motor neurons, leading to muscle weakness, paralysis, and death. Although significant progress has been made in understanding ALS, its molecular mechanisms remain complex and multifactorial. This review explores the potential convergent mechanisms underlying ALS pathogenesis, focusing on the roles of key proteins including NEK1, C21ORF2, cyclin F, VCP, and TDP-43. Recent studies suggest that mutations in C21ORF2 lead to the stabilization of NEK1, while cyclin F mutations activate VCP, resulting in TDP-43 aggregation. TDP-43 aggregation, a hallmark of ALS, impairs RNA processing and protein transport, both of which are essential for neuronal function. Furthermore, TDP-43 has emerged as a key player in DNA damage repair, translocating to DNA damage sites and recruiting repair proteins. Given that NEK1, VCP, and cyclin F are also involved in DNA repair, this review examines how these proteins may intersect to disrupt DNA damage repair mechanisms, contributing to ALS progression. Impaired DNA repair and protein homeostasis are suggested to be central downstream mechanisms in ALS pathogenesis. Ultimately, understanding the interplay between these pathways could offer novel insights into ALS and provide potential therapeutic targets. This review aims to highlight the emerging connections between protein aggregation, DNA damage repair, and cellular dysfunction in ALS, fostering a deeper understanding of its molecular basis and potential avenues for intervention.},
}

Humans
*Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology
*NIMA-Related Kinase 1/genetics/metabolism
*Valosin Containing Protein/genetics/metabolism
*Cyclins/genetics/metabolism
DNA-Binding Proteins/genetics/metabolism
Animals
DNA Damage
Mutation
DNA Repair

@article {pmid40281300,
year = {2025},
author = {Upadhayay, S and Soni, D and Dhureja, M and Temgire, P and Kumar, V and Arthur, R and Kumar, P},
title = {Role of Fibroblast Growth Factors in Neurological Disorders: Insight into Therapeutic Approaches and Molecular Mechanisms.},
journal = {Molecular neurobiology},
volume = {},
number = {},
pages = {},
pmid = {40281300},
issn = {1559-1182},
abstract = {In the last few decades, the incidence and progression of neurological disorders have consistently increased, which mainly occur due to environmental pollution, genetic abnormalities, and modern lifestyles. Several case reports suggested that these factors enhanced oxidative stress, mitochondrial dysfunction, inflammation, and apoptosis, leading to neurological disease. The pathophysiology of neurological disorders is still not understood, mainly due to the diversity within affected populations. Existing treatment options primarily provide symptomatic relief but frequently come with considerable side effects, including depression, anxiety, and restlessness. Fibroblast growth factors (FGFs) are key signalling molecules regulating various cellular functions, including cell proliferation, differentiation, electrical excitability, and injury responses. Hence, several investigations claimed a relationship between FGFs and neurological disorders, and their findings indicated that they could be used as therapeutic targets for neurological disorders. The FGFs are reported to activate various signalling pathways, including Ras/MAPK/PI3k/Akt, and downregulate the GSK-3β/NF-κB pathways responsible for anti-oxidant, anti-inflammatory, and anti-apoptotic effects. Therefore, researchers are interested in developing novel treatment options for neurological disorders. The emergence of unreported FGFs contributes to our understanding of their involvement in these conditions and encourages further exploration of innovative therapeutic approaches. All the data were obtained from published articles using PubMed, Web of Science, and Scopus databases using the search terms Fibroblast Growth Factor, PD, HD, AD, ALS, signalling pathways, and neurological disorders.},
}

@article {pmid40280271,
year = {2025},
author = {Kopalli, SR and Behl, T and Baldaniya, L and Ballal, S and Joshi, KK and Arya, R and Chaturvedi, B and Chauhan, AS and Verma, R and Patel, M and Jain, SK and Wal, A and Gulati, M and Koppula, S},
title = {Neuroadaptation in neurodegenerative diseases: compensatory mechanisms and therapeutic approaches.},
journal = {Progress in neuro-psychopharmacology & biological psychiatry},
volume = {},
number = {},
pages = {111375},
doi = {10.1016/j.pnpbp.2025.111375},
pmid = {40280271},
issn = {1878-4216},
abstract = {Progressive neuronal loss is a hallmark of neurodegenerative diseases including Alzheimer's, Parkinson's, Huntington's, and Amyotrophic Lateral Sclerosis (ALS), which cause cognitive and motor impairment. Delaying the onset and course of symptoms is largely dependent on neuroadaptation, the brain's ability to restructure in response to damage. The molecular, cellular, and systemic processes that underlie neuroadaptation are examined in this study. These mechanisms include gliosis, neurogenesis, synaptic plasticity, and changes in neurotrophic factors. Axonal sprouting, dendritic remodelling, and compensatory alterations in neurotransmitter systems are important adaptations observed in NDDs; nevertheless, these processes may shift to maladaptive plasticity, which would aid in the advancement of the illness. Amyloid and tau pathology-induced synaptic alterations in Alzheimer's disease emphasize compensatory network reconfiguration. Dopamine depletion causes a major remodelling of the basal ganglia in Parkinson's disease, and non-dopaminergic systems compensate. Both ALS and Huntington's disease rely on motor circuit rearrangement and transcriptional dysregulation to slow down functional deterioration. Neuroadaptation is, however, constrained by oxidative stress, compromised autophagy, and neuroinflammation, particularly in elderly populations. The goal of emerging therapy strategies is to improve neuroadaptation by pharmacologically modifying neurotrophic factors, neuroinflammation, and synaptic plasticity. Neurostimulation, cognitive training, and physical rehabilitation are instances of non-pharmacological therapies that support neuroplasticity. Restoring compensating systems may be possible with the use of stem cell techniques and new gene treatments. The goal of future research is to combine biomarkers and individualized medicines to maximize neuroadaptive responses and decrease the course of illness. In order to reduce neurodegeneration and enhance patient outcomes, this review highlights the dual function of neuroadaptation in NDDs and its potential as a therapeutic target.},
}

@article {pmid40279084,
year = {2025},
author = {Singh, P and Borkar, M and Doshi, G},
title = {Network pharmacology approach to unravel the neuroprotective potential of natural products: a narrative review.},
journal = {Molecular diversity},
volume = {},
number = {},
pages = {},
pmid = {40279084},
issn = {1573-501X},
abstract = {Aging is a slow and irreversible biological process leading to decreased cell and tissue functions with higher risks of multiple age-related diseases, including neurodegenerative diseases. It is widely accepted that aging represents the leading risk factor for neurodegeneration. The pathogenesis of these diseases involves complex interactions of genetic mutations, environmental factors, oxidative stress, neuroinflammation, and mitochondrial dysfunction, which complicate treatment with traditional mono-targeted therapies. Network pharmacology can help identify potential gene or protein targets related to neurodegenerative diseases. Integrating advanced molecular profiling technologies and computer-aided drug design further enhances the potential of network pharmacology, enabling the identification of biomarkers and therapeutic targets, thus paving the way for precision medicine in neurodegenerative diseases. This review article delves into the application of network pharmacology in understanding and treating neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and spinal muscular atrophy. Overall, this article emphasizes the importance of addressing aging as a central factor in developing effective disease-modifying therapies, highlighting how network pharmacology can unravel the complex biological networks associated with aging and pave the way for personalized medical strategies.},
}

@article {pmid40278411,
year = {2025},
author = {Di Sarno, A and Romano, F and Arianna, R and Serpico, D and Lavorgna, M and Savastano, S and Colao, A and Di Somma, C},
title = {Lipid Metabolism and Statin Therapy in Neurodegenerative Diseases: An Endocrine View.},
journal = {Metabolites},
volume = {15},
number = {4},
pages = {},
pmid = {40278411},
issn = {2218-1989},
abstract = {Background/aim: A growing body of evidence suggests a link between dyslipidemias and neurodegenerative diseases, highlighting the crucial role of lipid metabolism in the health of the central nervous system. The aim of our work was to provide an update on this topic, with a focus on clinical practice from an endocrinological point of view. Endocrinologists, being experts in the management of dyslipidemias, can play a key role in the prevention and treatment of neurodegenerative conditions, through precocious and effective lipid profile optimization. Methods: The literature was scanned to identify clinical trials and correlation studies on the association between dyslipidemia, statin therapy, and the following neurodegenerative diseases: Alzheimer's disease (AD), Parkisons's disease (PD), Multiple sclerosis (MS), and Amyotrophic lateral sclerosis (ALS). Results: Impaired lipid homeostasis, such as that frequently observed in patients affected by obesity and diabetes, is related to neurodegenerative diseases, such as AD, PD, and other cognitive deficits related to aging. AD and related dementias are now a real priority health problem. In the United States, there are approximately 7 million subjects aged 65 and older living with AD and related dementias, and this number is projected to grow to 12 million in the coming decades. Lipid-lowering therapy with statins is an effective strategy in reducing serum low-density lipoprotein cholesterol to normal range concentrations and, therefore, cardiovascular disease risk; moreover, statins have been reported to have a positive effect on neurodegenerative diseases. Conclusions: Several pieces of research have found inconsistent information following our review. There was no association between statin use and ALS incidence. More positive evidence has emerged regarding statin use and AD/PD. However, further large-scale prospective randomized control trials are required to properly understand this issue.},
}

@article {pmid40273110,
year = {2025},
author = {Souza, AA and Silva, STD and Régis, AMP and Aires, DN and Pondofe, KM and Melo, LP and Valentim, RAM and Lindquist, ARR and Macedo, LRD and Ribeiro, TS},
title = {Muscle strengthening in individuals with Amyotrophic Lateral Sclerosis: a systematic review with meta-analyses.},
journal = {PloS one},
volume = {20},
number = {4},
pages = {e0320788},
pmid = {40273110},
issn = {1932-6203},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/rehabilitation/therapy ; *Muscle Strength/physiology ; *Resistance Training/methods ; *Exercise Therapy/methods ; },
abstract = {Despite the observed benefits of properly prescribed exercises for people with Amyotrophic Lateral Sclerosis (ALS), the scarcity of studies and lack of consensus on the effects of muscle-strengthening exercises on this population has a negative impact on their rehabilitation. This study aimed to evaluate the effects of muscle-strengthening interventions in individuals with ALS. This systematic review of intervention studies included clinical trials that performed non-respiratory muscle strengthening in people with ALS compared to non-strengthening interventions, usual care, or placebo. Such studies were obtained from the MEDLINE, EMBASE, Cochrane Library, SPORTDiscus, and Physiotherapy Evidence Database databases, with no language or publication date restrictions. The outcomes considered were peripheral muscle strength, functionality, fatigue, and adverse events. The Physiotherapy Evidence Database scale was used to analyze the risk of bias, while the Grading of Recommendations Assessment, Development and Evaluation system was used to evaluate the quality of the evidence. Searches were conducted in October 2023 and eight studies were included, totaling 296 individuals. Seven of the eight studies showed superiority of the experimental intervention over the control, but this was not supported in the meta-analyses. Small sample size and high heterogeneity in the primary studies contributed significantly to the low quality of the evidence. There was no evidence of the superiority of interventions for muscle strengthening compared to interventions not aimed at strengthening, usual care, or placebo in terms of the outcomes analyzed immediately after the intervention. The quality of the evidence ranged from low to very low. Five of the studies evaluated adverse events, without reporting serious events. Interventions for muscle strengthening did not prove to be more effective when compared to the control group in the short term nor seem to produce serious adverse events. The low quality of the evidence indicates the need for studies with greater methodological rigor in this population, to more assertively assess the impacts of this intervention over the short, medium, and long term.},
}

Humans
*Amyotrophic Lateral Sclerosis/physiopathology/rehabilitation/therapy
*Muscle Strength/physiology
*Resistance Training/methods
*Exercise Therapy/methods

@article {pmid40272376,
year = {2025},
author = {Nguyen, THV and Ferron, F and Murakami, K},
title = {Neurotoxic Implications of Human Coronaviruses in Neurodegenerative Diseases: A Perspective from Amyloid Aggregation.},
journal = {ACS chemical biology},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschembio.5c00153},
pmid = {40272376},
issn = {1554-8937},
abstract = {Human coronaviruses (HCoVs) include seven species: HCoV-229E, HCoV-NL63, HCoV-OC43, HCoV-HKU1, MERS-CoV, SARS-CoV-1, and SARS-CoV-2. The last three, classified as Betacoronaviruses, are highly transmissible and have caused severe pandemics. HCoV infections primarily affect the respiratory system, leading to symptoms such as dry cough, fever, and breath shortness, which can progress to acute respiratory failure and death. Beyond respiratory effects, increasing evidence links HCoVs to neurological dysfunction. However, distinguishing direct neural complications from preexisting disorders, particularly in the elderly, remains challenging. This study examines the association between HCoVs and neurodegenerative diseases like Alzheimer disease, Parkinson disease, Lewy body dementia, amyotrophic lateral sclerosis, and Creutzfeldt-Jakob disease. It also presents the long-term neurological effects of HCoV infections and their differential impact across age groups and sexes. A key aspect of this study is the investigation of the sequence and structural similarities between amyloidogenic and HCoV spike proteins, which can provide insights into potential neuropathomechanisms.},
}

@article {pmid39778593,
year = {2025},
author = {Chen, Q and Chen, G and Wang, Q},
title = {Application of Network Pharmacology in the Treatment of Neurodegenerative Diseases with Traditional Chinese Medicine.},
journal = {Planta medica},
volume = {91},
number = {5},
pages = {226-237},
pmid = {39778593},
issn = {1439-0221},
support = {2023AFB677//the Natural Science Foundation of Hubei Province/ ; 2024AFB578//the Natural Science Foundation of Hubei Province/ ; 2023LYYYGZRP0003//the Intramural Research Program of Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology/ ; 2023LYYYSZRP0001//the Intramural Research Program of Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology/ ; },
mesh = {Humans ; *Medicine, Chinese Traditional/methods ; *Neurodegenerative Diseases/drug therapy ; *Network Pharmacology/methods ; *Drugs, Chinese Herbal/pharmacology/therapeutic use ; },
abstract = {In recent years, the incidence of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis, has exhibited a steadily rising trend, which has posed a major challenge to the global public health. Traditional Chinese medicine, with its multicomponent and multitarget characteristics, offers a promising approach to treating neurodegenerative diseases. However, comprehensively elucidating the complex mechanisms underlying traditional Chinese medicine formulations remains challenging. As an emerging systems biology method, network pharmacology has provided a vital tool for revealing the multitarget mechanisms of traditional Chinese medicine through high-throughput technologies, molecular docking, and network analysis. This paper reviews the advancements in the application of network pharmacology in treating neurodegenerative diseases using traditional Chinese medicine, analyzes the current status of relevant databases and technological methods, discusses the limitations, and proposes future directions to promote the modernization of traditional Chinese medicine and the development of precision medicine.},
}

Humans
*Medicine, Chinese Traditional/methods
*Neurodegenerative Diseases/drug therapy
*Network Pharmacology/methods
*Drugs, Chinese Herbal/pharmacology/therapeutic use

@article {pmid40271431,
year = {2025},
author = {Rana, A and Katiyar, A and Arun, A and Berrios, JN and Kumar, G},
title = {Natural sulfur compounds in mental health and neurological disorders: insights from observational and intervention studies.},
journal = {Frontiers in nutrition},
volume = {12},
number = {},
pages = {1534000},
doi = {10.3389/fnut.2025.1534000},
pmid = {40271431},
issn = {2296-861X},
abstract = {Over the years, the global disease burden of neurological disorders (NDs) and mental disorders (MDs) has significantly increased, making them one of the most critical concerns and challenges to human health. In pursuit of novel therapies against MD and ND, there has been a growing focus on nutrition and health. Dietary sulfur, primarily derived from various natural sources, plays a crucial role in numerous physiological processes, including brain function. This review offers an overview of the chemical composition of several natural sources of the sulfur-rich substances such as isothiocyanates, sulforaphane, glutathione, taurine, sulfated polysaccharides, allyl sulfides, and sulfur-containing amino acids, all of which have neuroprotective properties. A multitude of studies have documented that consuming foods that are high in sulfur enhances brain function by improving cognitive parameters and reduces the severity of neuropathology by exhibiting antioxidant and anti-inflammatory properties at the molecular level. In addition, the growing role of natural sulfur compounds in repairing endothelial dysfunction, compromising blood-brain barrier and improving cerebral blood flow, are documented here. Furthermore, this review covers the encouraging results of supplementing sulfur-rich diets in many animal models and clinical investigations, along with their molecular targets in MD, such as schizophrenia, depression, anxiety, bipolar disorder, and autism spectrum disorder, and ND, such as Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic Lateral Sclerosis (ALS), and Multiple Sclerosis (MS). The prospects of natural sulfur compounds show great promise as they have potential applications in nutraceuticals, medicines, and functional foods to enhance brain function and prevent diseases. However, additional research is required to clarify the mechanisms by which it works, enhance its bioavailability, and evaluate its long-term safety for broad use.},
}

@article {pmid40271071,
year = {2025},
author = {Luo, H and Wei, S and Fu, S and Han, L},
title = {Role of Achyranthes aspera in neurodegenerative diseases: current evidence and future directions.},
journal = {Frontiers in pharmacology},
volume = {16},
number = {},
pages = {1511011},
doi = {10.3389/fphar.2025.1511011},
pmid = {40271071},
issn = {1663-9812},
abstract = {Neurodegenerative diseases are caused by the progressive degeneration of neurons and/or their myelin sheaths, ultimately leading to cognitive and motor dysfunction. Due to their complex pathogenesis and the limited efficacy of therapeutic drugs, these diseases have attracted significant attention. Achyranthes aspera, belongs to family Amaranthaceae, has been extensively used in the traditional and folk medicines for the treatment of various ailments. Modern research has revealed that Achyranthes aspera possesses various pharmacological effects, including cardiocerebrovascular protection, immune regulation, antioxidation, and anti-aging. Furthermore, the neuroprotective effects of Achyranthes aspera have been confirmed by numerous scientific studies. This review focuses on the primary pharmacological effects and mechanisms of Achyranthes aspera in the prevention and treatment of neurodegenerative diseases, as well as their potential application prospects. This review aims to provide insights into the potential clinical applications and research directions of Achyranthes aspera in neurodegenerative diseases.},
}

@article {pmid39254482,
year = {2025},
author = {García-Parra, B and Guiu, JM and Povedano, M and Modamio, P},
title = {A scoping review of the role of managed entry agreements in upcoming drugs for amyotrophic lateral sclerosis: learning from the case of spinal muscular atrophy.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {26},
number = {1-2},
pages = {48-57},
doi = {10.1080/21678421.2024.2400522},
pmid = {39254482},
issn = {2167-9223},
mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/economics ; Humans ; *Muscular Atrophy, Spinal/drug therapy/economics ; },
abstract = {INTRODUCTION: The therapeutic options for spinal muscular atrophy (SMA) are encouraging. However, there is currently no cure for amyotrophic lateral sclerosis (ALS). The clinical and economic uncertainty surrounding innovative treatments for rare neurodegenerative diseases makes it necessary to understand managed entry agreements (MEAs). The aim of this study was to review whether models of MEAs in SMA could be extrapolated to ALS.

METHODS: We performed a scoping review with information on MEAs on SMA in Web of Science (WOS), PubMed, Lyfegen Library, the National Institute for Health and Care Excellence (NICE), and the Canadian Agency for Drugs and Technologies in Health (CADTH).

RESULTS: We found 45 results in WOS and PubMed. After an initial survey, 10 were reviewed to assess eligibility, and three were selected. We obtained 44 results from Lyfegen Library, and three results each from NICE and CADTH.

CONCLUSION: The main objective of MEAs is to reduce uncertainty in the financing of drugs with a high budgetary impact and clinical concerns, as is the case with drugs for SMA and ALS. While the information available on MEAs in SMA is scarce, some conceptual models are publicly available. MEAs for long-term treatments for SMA could be used for the design of MEAs in ALS because of their similarities in economic and clinical uncertainty.},
}

*Amyotrophic Lateral Sclerosis/drug therapy/economics
Humans
*Muscular Atrophy, Spinal/drug therapy/economics

@article {pmid40268233,
year = {2025},
author = {Basak, B and Holzbaur, ELF},
title = {Mitophagy in Neurons: Mechanisms Regulating Mitochondrial Turnover and Neuronal Homeostasis.},
journal = {Journal of molecular biology},
volume = {},
number = {},
pages = {169161},
doi = {10.1016/j.jmb.2025.169161},
pmid = {40268233},
issn = {1089-8638},
abstract = {Mitochondrial quality control is instrumental in regulating neuronal health and survival. The receptor-mediated clearance of damaged mitochondria by autophagy, known as mitophagy, plays a key role in controlling mitochondrial homeostasis. Mutations in genes that regulate mitophagy are causative for familial forms of neurological disorders including Parkinson's disease (PD) and Amyotrophic lateral sclerosis(ALS). PINK1/Parkin-dependent mitophagy is the best studied mitophagy pathway, while more recent work has brought to light additional mitochondrial quality control mechanisms that operate either in parallel to or independent of PINK1/Parkin mitophagy. Here, we discuss our current understanding of mitophagy mechanisms operating in neurons to govern mitochondrial homeostasis. We also summarize progress in our understanding of the links between mitophagic dysfunction and neurodegeneration and highlight the potential for therapeutic interventions to maintain mitochondrial health and neuronal function.},
}

@article {pmid40265276,
year = {2025},
author = {Mendonça, IP and Peixoto, CA},
title = {The Double-Edged Sword: The Complex Function of Enteric Glial Cells in Neurodegenerative Diseases.},
journal = {Journal of neurochemistry},
volume = {169},
number = {4},
pages = {e70069},
doi = {10.1111/jnc.70069},
pmid = {40265276},
issn = {1471-4159},
support = {CNPq;#301891/2022-2//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; IAM-PROEP# 005-FIO-22//Instituto Aggeu Magalhães/ ; },
mesh = {Humans ; *Neurodegenerative Diseases/pathology/metabolism ; *Neuroglia/metabolism/pathology/physiology ; Animals ; *Enteric Nervous System/pathology/metabolism ; },
abstract = {Over the past two decades, a growing number of studies have been conducted on the role of bidirectional communication through the gut-brain axis in the development of neurodegenerative diseases. These studies were driven by the curious fact that all of these diseases present varying degrees of intestinal involvement included in their wide range of symptoms. A population of cells belonging to the ENS, called enteric glial cells (EGCs), appears to actively participate in this communication between the intestine and the brain, but acting in a dualistic manner, sometimes in reactive gliosis releasing inflammatory mediators, sometimes promoting homeostasis and resilience in the face of inflammatory injuries. To date, the intracellular mechanisms that define the transcriptional profile expressed in EGCs in each situation have not yet been elucidated. This review proposes a discussion on: (1) the complex role of distinct phenotypes of enteric glial cells involved in neurodegenerative diseases, such as Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD) and multiple sclerosis (MS); and (2) innovative strategies such as IDO/TDO inhibitors, Brazil nuts, caffeic acid, polyphenols, among others, that act on EGCs and have the potential to treat neurodegenerative diseases.},
}

Humans
*Neurodegenerative Diseases/pathology/metabolism
*Neuroglia/metabolism/pathology/physiology
Animals
*Enteric Nervous System/pathology/metabolism

@article {pmid40256588,
year = {2024},
author = {Ahmady, H and Afrand, M and Motaqi, M and Meftahi, GH},
title = {Utilizing Sertoli Cell Transplantation as a Therapeutic Technique for the Management of Neurodegenerative Diseases.},
journal = {Archives of Razi Institute},
volume = {79},
number = {4},
pages = {701-710},
pmid = {40256588},
issn = {2008-9872},
mesh = {*Neurodegenerative Diseases/therapy ; Humans ; Male ; Animals ; *Sertoli Cells/transplantation ; },
abstract = {Neurodegenerative diseases (NDs), such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD), are defined by aberrant protein accumulation, brain atrophy, and gradual decline of neuronal function. Despite the considerable endeavors devoted to discovering treatments for NDs in recent decades, the demand for efficient therapeutic agents persists. Sertoli cells (SCs) play a crucial role in providing a supportive structure and environment for the development of germ cells. SCs, whether transplanted as xenogeneic or allogeneic cells, present a viable choice for enhancing graft persistence via the release of immunomodulatory and trophic factors, including neurturin (NTN), platelet-derived growth factor, Fas (CD95) ligand (FasL), glial-derived neurotrophic factor, interleukin 1 (IL1), brain-derived neurotrophic factor, interleukin 6 (IL6), transforming growth factors, and vascular growth factor, that protect replaced cells and tissues from the immune system. However, there is currently no cohesive evidence regarding the neuroprotective influence of the transplantation of SCs on NDs. Therefore, this review focuses on assessing stem cells' neuroprotective impact on neurodegenerative diseases in pre-clinical settings and presenting cohesive information. A comprehensive search was conducted between 2000 and 2022. In the identification stage, after a comprehensive search across databases, including Web of Science, Scopus, and PubMed/Medline, 103 papers were obtained. The search conducted in the present study yielded a total of nine relevant papers on the therapeutic effect of the transplantation of SCs on NDs. It was found that the transplantation of SCs exhibits a promising impact on enhancing the symptoms of neurological diseases in rats. The findings highlight the need for multiple standardized pre-clinical trials to find reliable information to confirm the utilization of the transplantation of SCs and the reduction of the symptoms of neurodegenerative diseases.},
}

*Neurodegenerative Diseases/therapy
Humans
Male
Animals
*Sertoli Cells/transplantation

@article {pmid40254133,
year = {2025},
author = {Turner-Ivey, B and Jenkins, DP and Carroll, SL},
title = {Multiple Roles for Neuregulins and their ERBB Receptors in Neurodegenerative Disease Pathogenesis and Therapy.},
journal = {The American journal of pathology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.ajpath.2025.03.012},
pmid = {40254133},
issn = {1525-2191},
abstract = {The role that neurotrophins such as nerve growth factor play in the pathogenesis of neurodegenerative diseases has long been appreciated. However, the neuregulin (NRG) family of growth factors and/or their ERBB receptors have also been implicated in the pathogenesis of conditions such as Alzheimer's disease (AD), frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). In this review, we consider (1) the structural variability of NRG isoforms generated by alternative RNA splicing, the use of multiple promoters and proteolysis and the impact that this structural variability has on neuronal and glial physiology during development and adulthood. We discuss (2) the NRG receptors ERBB2, ERBB3 and ERBB4, how activation of each of these receptors further diversifies NRG actions in the central nervous system and how dementia-related proteins such as γ-secretase modulate the action of NRGs and their ERBB receptors. We then (3) turn to the abnormalities in NRG and ERBB expression and function evident in human AD and mouse AD models, how these abnormalities affect brain function, and attempts to use NRGs to treat AD. Finally, (4) we discuss NRG effects on the survival and function of neurons relevant to FTLD and ALS, alterations in NRG/ERBB signaling identified in these conditions and the recent discovery of multiple human pedigrees in which autosomal dominant FTLD/ALS potentially results from point mutations in ERBB4.},
}

@article {pmid40253599,
year = {2025},
author = {Malik, M and Bhatti, T and Hodson-Tole, E and Onambele-Pearson, G and Chaouch, A},
title = {Physical activity in amyotrophic lateral sclerosis: a systematic review of the methodologies used to assess a possible association.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-18},
doi = {10.1080/21678421.2025.2488298},
pmid = {40253599},
issn = {2167-9223},
abstract = {Growing evidence suggests that strenuous physical activity (PA) may be associated with an increased risk of developing Amyotrophic Lateral Sclerosis (ALS), a fatal neurodegenerative disease. However, there are inconsistent findings across studies that may reduce our understanding of any potential associations. We propose that these differences may reflect the tools used to record historical PA. We conducted a systematic review evaluating the risk of developing ALS due to PA. The inclusion criteria were met by 22/113 studies, and an association between increasing PA and ALS was found in 15 studies. Studies that found a positive association were more likely to have longer recall periods and convert data into Metabolic Equivalent of Task values. Studies that did not find an association with increasing PA were more likely to use questionnaires with no validity or reliability data. Questionnaires with validity data all showed at least a moderate correlation of PA compared to objective measures, with reliability ranging from poor to good. Study designs included prospective cohort and case-control, which may also contribute to heterogeneity in findings. This work highlights the need for consensus on the type of questionnaire to use to assess potential associations between PA and ALS.},
}

@article {pmid40252666,
year = {2025},
author = {Balendra, R and Sreedharan, J and Hallegger, M and Luisier, R and Lashuel, HA and Gregory, JM and Patani, R},
title = {Amyotrophic lateral sclerosis caused by TARDBP mutations: from genetics to TDP-43 proteinopathy.},
journal = {The Lancet. Neurology},
volume = {24},
number = {5},
pages = {456-470},
doi = {10.1016/S1474-4422(25)00109-7},
pmid = {40252666},
issn = {1474-4465},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; *DNA-Binding Proteins/genetics/metabolism ; *TDP-43 Proteinopathies/genetics/pathology ; *Mutation/genetics ; },
abstract = {Mutations in the TARDBP gene, which encodes the TDP-43 protein, account for only 3-5% of familial cases of amyotrophic lateral sclerosis and less than 1% of cases that are apparently idiopathic. However, the discovery of neuronal inclusions of TDP-43 as the neuropathological hallmark in the majority of cases of amyotrophic lateral sclerosis has transformed our understanding of the pathomechanisms underlying neurodegeneration. An individual TARDBP mutation can cause phenotypic heterogeneity. Most mutations lie within the C-terminus of the TDP-43 protein. In pathological conditions, TDP-43 is mislocalised from the nucleus to the cytoplasm, where it can be phosphorylated, cleaved, and form insoluble aggregates. This mislocalisation leads to dysfunction of downstream pathways of RNA metabolism, proteostasis, mitochondrial function, oxidative stress, axonal transport, and local translation. Biomarkers for TDP-43 dysfunction and targeted therapies are being developed, justifying cautious optimism for personalised medicine approaches that could rescue the downstream effects of TDP-43 pathology.},
}

Humans
*Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism
*DNA-Binding Proteins/genetics/metabolism
*TDP-43 Proteinopathies/genetics/pathology
*Mutation/genetics

@article {pmid40245393,
year = {2025},
author = {Musson, LS and Mitic, N and Leigh-Valero, V and Onambele-Pearson, G and Knox, L and Steyn, FJ and Holdom, CJ and Dick, TJ and van Eijk, RP and van Unnik, JW and Botman, LC and Beswick, E and Murray, D and Griffiths, A and McDermott, C and Hobson, E and Chaouch, A and Hodson-Tole, E},
title = {The Use of Digital Devices to Monitor Physical Behavior in Motor Neuron Disease: Systematic Review.},
journal = {Journal of medical Internet research},
volume = {27},
number = {},
pages = {e68479},
doi = {10.2196/68479},
pmid = {40245393},
issn = {1438-8871},
mesh = {Humans ; *Exercise ; *Motor Neuron Disease/diagnosis/physiopathology ; *Wearable Electronic Devices ; },
abstract = {BACKGROUND: Motor neuron disease (MND) is a progressive and incurable neurodegenerative disease. The Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) is the primary clinical tool for assessing disease severity and progression in MND. However, despite its widespread use, it does not adequately capture the extent of physical function decline. There is an urgent need for sensitive measures of disease progression that can be used to robustly evaluate new treatments. Measures of physical function derived from digital devices are beginning to be used to assess disease progression. There is value in establishing a consensus approach to standardizing the use of such devices.

OBJECTIVE: We aimed to explore how digital devices are being used to quantify free-living physical behavior in MND. We evaluated the feasibility and assessed the implications for monitoring physical behavior for future clinical trials and clinical practice.

METHODS: Systematic searches of 4 databases were performed in October 2023 and June 2024. Peer-reviewed English-language articles (including preprints) that examined how people living with MND used digital devices to assess their free-living physical behavior were included. Study reporting quality was assessed using a 22-item checklist (maximum possible score=44 points).

RESULTS: In total, 12 articles met the inclusion criteria for data extraction. All studies were longitudinal and observational in design, but data collection, analysis, and reporting protocols varied. Quality assessment scores ranged between 19 and 40 points. Sample sizes ranged between 10 and 376 people living with MND at baseline, declining over the course of the study. Most studies used an accelerometer device worn on the wrist, chest, hip, or ankle. Participants were typically asked to continuously wear devices for 1 to 8 days at 1- to 4-month intervals, with studies running for 12 weeks to 24 months. Some studies asked participants to wear the device continuously for the full duration. Studies derived traditional end points focusing on duration, intensity, and frequency of physical activity or nontraditional end points focusing on features of an individual's movement patterns. The correlation coefficients (r) between physical behavior end points and ALSFRS-R ranged from 0.31 to 0.78. Greater monitoring frequencies and improved end point sensitivity were shown to provide smaller sample size requirements and shorter durations for hypothetical clinical trials. People living with MND found using devices acceptable and reported a low burden. Adherence assessed in 8 (67%) studies was good, ranging from approximately 86% to 96%, with differences evident between wear locations. The perspectives of other end users and implications on clinical practice were not explored.

CONCLUSIONS: Remote monitoring of free-living physical behavior in MND is in its infancy but has the potential to quantify physical function. It is essential to develop a consensus statement, working toward agreed and standardized methods for data collection, analysis, and reporting.},
}

Humans
*Exercise
*Motor Neuron Disease/diagnosis/physiopathology
*Wearable Electronic Devices

@article {pmid40244061,
year = {2025},
author = {Tseriotis, VS and Liampas, A and Lazaridou, IZ and Karachrysafi, S and Vavougios, GD and Hadjigeorgiou, GM and Papamitsou, T and Kouvelas, D and Arnaoutoglou, M and Pourzitaki, C and Mavridis, T},
title = {Repulsive Guidance Molecule-A as a Therapeutic Target Across Neurological Disorders: An Update.},
journal = {International journal of molecular sciences},
volume = {26},
number = {7},
pages = {},
pmid = {40244061},
issn = {1422-0067},
mesh = {Humans ; Animals ; *Nervous System Diseases/metabolism/drug therapy ; *Nerve Tissue Proteins/metabolism/antagonists & inhibitors/genetics ; *GPI-Linked Proteins/metabolism/antagonists & inhibitors/genetics ; Molecular Targeted Therapy ; Neurodegenerative Diseases/metabolism/drug therapy ; },
abstract = {Repulsive guidance molecule-a (RGMa) has emerged as a significant therapeutic target in a variety of neurological disorders, including neurodegenerative diseases and acute conditions. This review comprehensively examines the multifaceted role of RGMa in central nervous system (CNS) pathologies such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, neuromyelitis optica spectrum disorder, spinal cord injury, stroke, vascular dementia, auditory neuropathy, and epilepsy. The mechanisms through which RGMa contributes to neuroinflammation, neuronal degeneration, and impaired axonal regeneration are herein discussed. Evidence from preclinical studies associate RGMa overexpression with negative outcomes, such as increased neuroinflammation and synaptic loss, while RGMa inhibition, particularly the use of agents like elezanumab, has shown promise in enhancing neuronal survival and functional recovery. RGMa's responses concerning immunomodulation and neurogenesis highlight its potential as a therapeutic avenue. We emphasize RGMa's critical role in CNS pathology and its potential to pave the way for innovative treatment strategies in neurological disorders. While preclinical findings are encouraging so far, further clinical trials are needed to validate the safety and efficacy of RGMa-targeted therapies.},
}

Humans
Animals
*Nervous System Diseases/metabolism/drug therapy
*Nerve Tissue Proteins/metabolism/antagonists & inhibitors/genetics
*GPI-Linked Proteins/metabolism/antagonists & inhibitors/genetics
Molecular Targeted Therapy
Neurodegenerative Diseases/metabolism/drug therapy

@article {pmid40243699,
year = {2025},
author = {Xu, R and Kang, Q and Yang, X and Yi, P and Zhang, R},
title = {Unraveling Molecular Targets for Neurodegenerative Diseases Through Caenorhabditis elegans Models.},
journal = {International journal of molecular sciences},
volume = {26},
number = {7},
pages = {},
pmid = {40243699},
issn = {1422-0067},
support = {32270739//National Natural Science Foundation of China/ ; },
mesh = {*Caenorhabditis elegans/genetics/metabolism ; Animals ; *Neurodegenerative Diseases/metabolism/genetics/drug therapy/pathology ; *Disease Models, Animal ; Humans ; Caenorhabditis elegans Proteins/metabolism/genetics ; },
abstract = {Neurodegenerative diseases (NDDs), including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and prion disease, represent a group of age-related disorders that pose a growing and formidable challenge to global health. Despite decades of extensive research that has uncovered key genetic factors and biochemical pathways, the precise molecular mechanisms underlying these diseases and effective therapeutic strategies remain elusive. Caenorhabditis elegans (C. elegans) has emerged as a powerful model organism for studying NDDs due to its unique biological features such as genetic tractability, conserved molecular pathways, and ease of high-throughput screening. This model provides an exceptional platform for identifying molecular targets associated with NDDs and developing novel therapeutic interventions. This review highlights the critical role of C. elegans in elucidating the complex molecular mechanisms of human NDDs, with a particular focus on recent advancements and its indispensable contributions to the discovery of molecular targets and therapeutic strategies for these NDDs.},
}

*Caenorhabditis elegans/genetics/metabolism
Animals
*Neurodegenerative Diseases/metabolism/genetics/drug therapy/pathology
*Disease Models, Animal
Humans
Caenorhabditis elegans Proteins/metabolism/genetics

@article {pmid40243463,
year = {2025},
author = {Fan, X and Diao, W and Wang, H and Yin, X and Qian, W},
title = {Interferon Regulatory Factors as a Potential Therapeutic Target for Neuroinflammation: A Focus on Alzheimer's Disease.},
journal = {International journal of molecular sciences},
volume = {26},
number = {7},
pages = {},
pmid = {40243463},
issn = {1422-0067},
support = {82473926//National Natural Science Foundation of China/ ; 81872875//National Natural Science Foundation of China/ ; 81170317//National Natural Science Foundation of China/ ; 81473218//National Natural Science Foundation of China/ ; 81503077//National Natural Science Foundation of China/ ; JC2023042//the project of Nantong Natural Science Foundation/ ; },
mesh = {Humans ; *Alzheimer Disease/metabolism/drug therapy/pathology ; Animals ; *Interferon Regulatory Factors/metabolism/genetics ; *Neuroinflammatory Diseases/metabolism/drug therapy ; Signal Transduction ; Inflammation/metabolism ; },
abstract = {Interferon Regulatory Factors (IRFs) are critical modulators of immune and inflammatory responses, yet their roles in Alzheimer's disease (AD) and other neurodegenerative disorders remain incompletely understood. While IRFs are recognized for their regulatory functions in neuroinflammation, microglial activation, and neuronal survival, their dual roles as both drivers of pathological inflammation and mediators of neuroprotective pathways underscore a sophisticated regulatory paradox in neurodegenerative disorders. This review aims to synthesize current evidence on IRF-mediated neuroinflammation in AD and related diseases, focusing on the multifaceted functions of key IRF family members, including IRF1, IRF3, and IRF7. We critically evaluate their divergent roles: IRF1 and IRF3, for instance, exacerbate neuroinflammatory cascades and amyloid-beta (Aβ) pathology in AD, whereas IRF7 may paradoxically suppress inflammation under specific conditions. Additionally, we explore IRF dysregulation in Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, and Huntington's disease, emphasizing shared and distinct mechanisms across neurodegenerative disorders. Restoring IRF balance through genetic manipulation, small-molecule inhibitors, or microbiome-derived modulators could attenuate neuroinflammation, enhance Aβ clearance, and protect neuronal integrity. Ultimately, this work provides a framework for future research to harness IRF signaling pathways in the development of precision therapies for AD and other neurodegenerative diseases.},
}

Humans
*Alzheimer Disease/metabolism/drug therapy/pathology
Animals
*Interferon Regulatory Factors/metabolism/genetics
*Neuroinflammatory Diseases/metabolism/drug therapy
Signal Transduction
Inflammation/metabolism

@article {pmid40234983,
year = {2025},
author = {Xie, Q and Li, K and Chen, Y and Li, Y and Jiang, W and Cao, W and Yu, H and Fan, D and Deng, B},
title = {Gene therapy breakthroughs in ALS: a beacon of hope for 20% of ALS patients.},
journal = {Translational neurodegeneration},
volume = {14},
number = {1},
pages = {19},
pmid = {40234983},
issn = {2047-9158},
support = {81901273//National Natural Science Foundation of China/ ; ZCLY24H0903//Natural Science Foundation of Zhejiang Province/ ; },
mesh = {*Amyotrophic Lateral Sclerosis/therapy/genetics ; Humans ; *Genetic Therapy/methods/trends ; Animals ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease that remains incurable. Although the etiologies of ALS are diverse and the precise pathogenic mechanisms are not fully understood, approximately 20% of ALS cases are caused by genetic factors. Therefore, advancing targeted gene therapies holds significant promise, at least for the 20% of ALS patients with genetic etiologies. In this review, we summarize the main strategies and techniques of current ALS gene therapies based on ALS risk genes, and review recent findings from animal studies and clinical trials. Additionally, we highlight ALS-related genes with well-understood pathogenic mechanisms and the potential of numerous emerging gene-targeted therapeutic approaches for ALS.},
}

*Amyotrophic Lateral Sclerosis/therapy/genetics
Humans
*Genetic Therapy/methods/trends
Animals

@article {pmid40234116,
year = {2025},
author = {McHale-Owen, H and Faller, KME and Chaytow, H and Gillingwater, TH},
title = {Phosphoglycerate kinase 1 as a therapeutic target in neurological disease.},
journal = {Trends in molecular medicine},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.molmed.2025.03.008},
pmid = {40234116},
issn = {1471-499X},
abstract = {Phosphoglycerate kinase 1 (PGK1) is a highly conserved enzyme that catalyzes the initial ATP-producing step in glycolysis. Improving cellular energy production by increasing PGK1 activity may be beneficial in multiple neurological conditions where cell metabolism is dysregulated, including Parkinson's disease (PD) and motor neuron disease (MND). This review examines recent evidence that suggests increasing PGK1 activity may be beneficial in multiple neurological conditions and discusses the current challenges surrounding the development of PGK1-focused therapies. PGK1 has considerable therapeutic potential, but novel PGK1 activators are needed to maximize the benefit for patients.},
}

@article {pmid40232582,
year = {2025},
author = {Mehrnoosh, F and Rezaei, D and Pakmehr, SA and Nataj, PG and Sattar, M and Shadi, M and Ali-Khiavi, P and Zare, F and Hjazi, A and Al-Aouadi, RFA and Sapayev, V and Zargari, F and Alkhathami, AG and Ahmadzadeh, R and Khedmatgozar, M and Hamzehzadeh, S},
title = {The role of Panax ginseng in neurodegenerative disorders: mechanisms, benefits, and future directions.},
journal = {Metabolic brain disease},
volume = {40},
number = {4},
pages = {183},
pmid = {40232582},
issn = {1573-7365},
mesh = {Humans ; *Panax ; *Neurodegenerative Diseases/drug therapy/metabolism ; Animals ; *Ginsenosides/therapeutic use/pharmacology ; *Neuroprotective Agents/therapeutic use/pharmacology ; *Plant Extracts/therapeutic use/pharmacology ; Oxidative Stress/drug effects ; },
abstract = {Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS), Multiple sclerosis (MS), and Huntington's disease (HD) represent a growing global health challenge, especially with aging populations. Characterized by progressive neuronal loss, these diseases lead to cognitive, motor, and behavioral impairments, significantly impacting patients' quality of life. Current therapies largely address symptoms without halting disease progression, underscoring the need for innovative, disease-modifying treatments. Ginseng, a traditional herbal medicine with well-known adaptogenic and neuroprotective properties, has gained attention as a potential therapeutic agent for neurodegeneration. Rich in bioactive compounds called ginsenosides, ginseng exhibits antioxidant, anti-inflammatory, and anti-apoptotic effects, making it a promising candidate for addressing the complex pathology of neurodegenerative diseases. Recent studies demonstrate that ginsenosides modulate disease-related processes such as oxidative stress, protein aggregation, mitochondrial dysfunction, and inflammation. In AD models, ginsenosides have been shown to reduce amyloid-beta accumulation and tau hyperphosphorylation, while in PD, they help protect dopaminergic neurons and mitigate motor symptoms. Ginseng's effects in ALS, MS, and HD models include improving motor function, extending neuronal survival, and reducing cellular toxicity. This review provides a comprehensive overview of the neuroprotective mechanisms of ginseng, emphasizing its therapeutic potential across various neurodegenerative diseases and discussing future research directions for its integration into clinical practice.},
}

Humans
*Panax
*Neurodegenerative Diseases/drug therapy/metabolism
Animals
*Ginsenosides/therapeutic use/pharmacology
*Neuroprotective Agents/therapeutic use/pharmacology
*Plant Extracts/therapeutic use/pharmacology
Oxidative Stress/drug effects

@article {pmid40222791,
year = {2025},
author = {Bhardwaj, I and Singh, S and Ansari, AH and Rai, SP and Singh, D},
title = {Effect of stress on neuronal cell: Morphological to molecular approach.},
journal = {Progress in brain research},
volume = {291},
number = {},
pages = {469-502},
doi = {10.1016/bs.pbr.2025.01.010},
pmid = {40222791},
issn = {1875-7855},
mesh = {Humans ; Animals ; *Neurons/pathology/metabolism/physiology ; *Stress, Psychological/pathology/metabolism ; *Brain/pathology ; },
abstract = {Stress can be characterized as any perceived or actual threat that necessitates compensatory actions to maintain homeostasis. It can alter an organism's behavior over time by permanently altering the composition and functionality of brain circuitry. The amygdala and prefrontal cortex are two interrelated brain regions that have been the focus of initial research on stress and brain structural and functional plasticity, with the hippocampus serving as the entry point for most of this knowledge. Prolonged stress causes significant morphological alterations in important brain regions such as the hippocampus, amygdala, and prefrontal cortex. Memory, learning, and emotional regulation are among the cognitive functions that are adversely affected by these changes, including neuronal shrinkage, dendritic retraction, and synaptic malfunction. Stress perturbs the equilibrium of neurotransmitters, neuronal plasticity, and mitochondrial function at the molecular level. On the other hand, chronic stress negatively impacts physiology and can result in neuropsychiatric diseases. Recent molecular research has linked various epigenetic processes, such as DNA methylation, histone modifications, and noncoding RNAs, to the dysregulation of genes in the impacted brain circuits responsible for the pathophysiology of chronic stress. Numerous disorders, including neurodegenerative diseases (NDDs) including Alzheimer's, amyotrophic lateral sclerosis, Friedreich's ataxia, Huntington's disease, multiple sclerosis, and Parkinson's disease, have been linked to oxidative stress as a possible cause.},
}

Humans
Animals
*Neurons/pathology/metabolism/physiology
*Stress, Psychological/pathology/metabolism
*Brain/pathology

@article {pmid40216201,
year = {2025},
author = {Cagalinec, M and Adnan, M and Borecka, S and Bultynck, G and Choubey, V and Yanovsky-Dagan, S and Ezer, S and Gasperikova, D and Harel, T and Jurkovicova, D and Kaasik, A and Liévens, JC and Maurice, T and Peviani, M and Richard, EM and Skoda, J and Skopkova, M and Tarot, P and Van Gorp, R and Zvejniece, L and Delprat, B},
title = {Improving mitochondria-associated endoplasmic reticulum membranes integrity as converging therapeutic strategy for rare neurodegenerative diseases and cancer.},
journal = {Biochimica et biophysica acta. Molecular cell research},
volume = {},
number = {},
pages = {119954},
doi = {10.1016/j.bbamcr.2025.119954},
pmid = {40216201},
issn = {1879-2596},
abstract = {Membrane contact sites harbor a distinct set of proteins with varying biological functions, thereby emerging as hubs for localized signaling nanodomains underlying adequate cell function. Here, we will focus on mitochondria-associated endoplasmic reticulum membranes (MAMs), which serve as hotspots for Ca[2+] signaling, redox regulation, lipid exchange, mitochondrial quality and unfolded protein response pathway. A network of MAM-resident proteins contributes to the structural integrity and adequate function of MAMs. Beyond endoplasmic reticulum (ER)-mitochondrial tethering proteins, MAMs contain several multi-protein complexes that mediate the transfer of or are influenced by Ca[2+], reactive oxygen species and lipids. Particularly, IP3 receptors, intracellular Ca[2+]-release channels, and Sigma-1 receptors (S1Rs), ligand-operated chaperones, serve as important platforms that recruit different accessory proteins and intersect with these local signaling processes. Furthermore, many of these proteins are directly implicated in pathophysiological conditions, where their dysregulation or mutation is not only causing diseases such as cancer and neurodegeneration, but also rare genetic diseases, for example familial Parkinson's disease (PINK1, Parkin, DJ-1), familial Amyotrophic lateral sclerosis (TDP43), Wolfram syndrome1/2 (WFS1 and CISD2), Harel-Yoon syndrome (ATAD3A). In this review, we will discuss the current state-of-the-art regarding the molecular components, protein platforms and signaling networks underlying MAM integrity and function in cell function and how their dysregulation impacts MAMs, thereby driving pathogenesis and/or impacting disease burden. We will highlight how these insights can generate novel, potentially therapeutically relevant, strategies to tackle disease outcomes by improving the integrity of MAMs and the signaling processes occurring at these membrane contact sites.},
}

@article {pmid40213632,
year = {2025},
author = {Dezawa, M},
title = {Macrophage- and pluripotent-like reparative Muse cells are unique endogenous stem cells distinct from other somatic stem cells.},
journal = {Frontiers in bioengineering and biotechnology},
volume = {13},
number = {},
pages = {1553382},
pmid = {40213632},
issn = {2296-4185},
abstract = {Muse cells are endogenous reparative stem cells with dual characteristics: pluripotent-like and macrophage-like. They can be identified by the pluripotent surface marker stage-specific embryonic antigen-3-positive (SSEA-3 (+)) cells in the bone marrow, peripheral blood, and various organs, including the umbilical cord and amnion. Muse cells can differentiate into ectodermal, endodermal, and mesodermal lineage cells, self-renew, and selectively migrate to damaged sites by sensing one of the universal tissue damage signals, sphingosine-1-phosphate (S1P). At these sites, they phagocytose damaged/apoptotic cells and differentiate into the same cell type as the phagocytosed cells. In this manner, Muse cells replace damaged/apoptotic cells with healthy, functioning cells, thereby repairing tissues. Due to their specific immunosuppressive and immunotolerant mechanism, clinical trials have been conducted for acute myocardial infarction (AMI), subacute ischemic stroke, epidermolysis bullosa, amyotrophic lateral sclerosis (ALS), cervical spinal cord injury, neonatal hypoxic-ischemic encephalopathy (HIE), and COVID-19 acute respiratory distress syndrome. These trials involved the intravenous injection of ∼1.5 × 10[7] donor Muse cells without human leukocyte antigen (HLA) matching or immunosuppressant treatment, and they demonstrated safety and therapeutic efficacy. Thus, donor Muse cell treatment does not require gene manipulation, differentiation induction, or surgical intervention. These unique characteristics distinguish Muse cells from other somatic stem cells, such as mesenchymal stem cells, VSEL stem cells, and marrow-isolated adult multi-lineage inducible (MIAMI) cells.},
}

@article {pmid40209696,
year = {2025},
author = {Hawas, Y and Hamad, AA and Meshref, M and Elbehary, M and Mohamed, RG and Elshahat, A and Mabrouk, MA and Nashwan, AJ and Fouda, BH},
title = {Clinical Features, Diagnostic Implications, And Outcomes of Amyotrophic Lateral Sclerosis and Myasthenia Gravis Overlap Syndrome: A Systematic Review.},
journal = {Medical principles and practice : international journal of the Kuwait University, Health Science Centre},
volume = {},
number = {},
pages = {1-18},
doi = {10.1159/000545806},
pmid = {40209696},
issn = {1423-0151},
abstract = {OBJECTIVE: This review aims to summarize the current evidence of reported myasthenia gravis (MG) and amyotrophic lateral sclerosis (ALS) overlap syndrome regarding clinical and laboratory features, diagnostic implications, management, outcomes, and comorbid conditions to raise awareness among healthcare providers and aid in proper care provision.

METHODS: Recently, a few cases of an unusual association between both diseases have been reported. PubMed, Scopus, and Web of Science were searched from inception until May 2024 to identify eligible studies. After the screening and data extraction, 20 studies with 42 cases suffering from ALS and MG were included.

RESULTS: 42 cases were categorized into four groups as follows: The first group had 26 cases with MG onset (range 26-82 years) preceding ALS (range 46-83 years). The second group had 9 cases with ALS (range 34-89) preceding MG (range 40-89 years). The third group comprised 5 cases of ALS with positive acetylcholine receptor antibodies but without clinical manifestations of MG. The fourth group involved 2 cases of ALS with initial ocular symptoms that were unresponsive to MG treatments.

CONCLUSION: The onset of new ptosis or diplopia in ALS patients should prompt clinicians to consider the possibility of a coexisting condition or alternative diagnosis. Additionally, positive acetylcholine receptor antibodies alone are insufficient to diagnose MG if ALS coexists. In patients with ALS, repetitive nerve stimulation tests may be less sensitive for detecting MG. Thus, diagnosing MG in ALS patients should rely on clinical presentation and response to empirical treatment.},
}

@article {pmid40209306,
year = {2025},
author = {Meanti, R and Bresciani, E and Rizzi, L and Molteni, L and Coco, S and Omeljaniuk, RJ and Torsello, A},
title = {Cannabinoid Receptor 2 (CB2R) as potential target for the pharmacological treatment of neurodegenerative diseases.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {186},
number = {},
pages = {118044},
doi = {10.1016/j.biopha.2025.118044},
pmid = {40209306},
issn = {1950-6007},
mesh = {Humans ; *Receptor, Cannabinoid, CB2/metabolism/agonists ; *Neurodegenerative Diseases/drug therapy/metabolism ; Animals ; Endocannabinoids/metabolism ; Molecular Targeted Therapy ; Cannabinoid Receptor Agonists/therapeutic use ; },
abstract = {The endocannabinoid system (ECS) is a ubiquitous physiological system that plays a crucial role in maintaining CNS homeostasis and regulating its functions. It includes cannabinoid receptors (CBRs), endogenous cannabinoids (eCBs), and the enzymes responsible for their synthesis and degradation. In recent years, growing evidence has highlighted the therapeutic potential of the ECS and CBRs, in a wide range of severe diseases and pathological conditions, including Alzheimer's and Parkinson's diseases, Amyotrophic Lateral Sclerosis, Multiple Sclerosis, Huntington's Disease, HIV-1 associated neurocognitive disorders, neuropathic pain and migraine. Targeting the cannabinoid type 2 receptor (CB2R) has gained attention due to its ability to (i) mitigate neuroinflammatory responses, (ii) regulate mitochondrial function and (iii) provide trophic support, all without eliciting the psychotropic actions associated with CB1R activation. This review aims to explore the potential of CB2R modulation as a strategy for the prevention and treatment of neurologic disorders, exploring both preclinical and clinical findings.},
}

Humans
*Receptor, Cannabinoid, CB2/metabolism/agonists
*Neurodegenerative Diseases/drug therapy/metabolism
Animals
Endocannabinoids/metabolism
Molecular Targeted Therapy
Cannabinoid Receptor Agonists/therapeutic use

@article {pmid40205152,
year = {2025},
author = {Mohan, M and Mannan, A and Singh, TG},
title = {Unravelling the role of protein kinase R (PKR) in neurodegenerative disease: a review.},
journal = {Molecular biology reports},
volume = {52},
number = {1},
pages = {377},
pmid = {40205152},
issn = {1573-4978},
mesh = {Humans ; *eIF-2 Kinase/metabolism/genetics ; *Neurodegenerative Diseases/metabolism/genetics ; Animals ; Parkinson Disease/metabolism/genetics ; Huntington Disease/genetics/metabolism ; Alzheimer Disease/metabolism/genetics ; Mitochondria/metabolism ; },
abstract = {Protein Kinase R is an essential regulator of many cell activities and belongs to one of the largest and most functionally complex gene families. These are found all over the body, and by adding phosphate groups to the substrate proteins, they regulate their activity and coordinate the action of almost all cellular processes. Recent research has illuminated the involvement of PKR in the pathogenesis of neurodegenerative disorders (NDs), thereby expanding our understanding of intricate molecular mechanisms underlying disease progression. Through their inhibition or activation, they hold potential therapeutic targets for the pathogenesis or protection of NDs. In the case of AD (AD), PKR contributes to the protection or elevation of Aβ accumulation, neuroinflammation, synaptic plasticity alterations, and neuronal excitability. Similarly, in Parkinson's disease (PD), PKR again has a dual role in dopaminergic neuronal loss, gene mutations, and mitochondrial dysfunction via various pathways. Notably, neuronal excitotoxicity, as well as genetic mutations, have been linked to ALS. In Huntington's disease (HD), PKR is associated with decreased or increased mutated genes, striatal neuron degeneration, neuroinflammation, and excitotoxicity. This review emphasizes strategies that target PKR for the treatment of neurodegenerative disorders. Doing so offers valuable insights that can guide future research endeavors and the development of innovative therapeutic approaches.},
}

Humans
*eIF-2 Kinase/metabolism/genetics
*Neurodegenerative Diseases/metabolism/genetics
Animals
Parkinson Disease/metabolism/genetics
Huntington Disease/genetics/metabolism
Alzheimer Disease/metabolism/genetics
Mitochondria/metabolism

@article {pmid40202704,
year = {2025},
author = {Oyovwi, MO and Chijiokwu, EA and Ben-Azu, B and Atere, AD and Joseph, UG and Ogbutor, UG and Udi, OA},
title = {Potential Roles of Natural Antioxidants in Modulating Neurodegenerative Disease Pathways.},
journal = {Molecular neurobiology},
volume = {},
number = {},
pages = {},
pmid = {40202704},
issn = {1559-1182},
abstract = {Neurodegenerative diseases, including Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis, are increasingly prevalent among aging populations. Oxidative stress contributes to these diseases, leading to cellular damage and neuronal death. Natural antioxidants are being explored as preventive measures. This study aims to assess the effectiveness of natural antioxidants in delaying the onset or progression of neurodegenerative diseases by identifying their specific mechanisms of action. A comprehensive review of existing literature was conducted, focusing on studies that examine the role of natural antioxidants in neuroprotection. Key natural antioxidants, including flavonoids, polyphenls, vitamins C and E, and omega-3 fatty acids, were reviewed and analyzed for their bioavailability, mechanisms of action, and outcomes in both in vitro and in vivo studies. Additionally, clinical trials involving human subjects were considered to provide insights into the translational implications of antioxidant consumption. The findings suggest that several natural antioxidants exhibit neuroprotective properties by modulating oxidative stress, reducing inflammation, and promoting neuronal survival. For instance, flavonoids such as quercetin and resveratrol have shown promise in enhancing cognitive function and mitigating the pathophysiological alterations associated with neurodegeneration. In clinical studies, higher intakes of dietary antioxidants were correlated with a reduced risk of developing neurodegenerative disorders. Natural antioxidants offer potential for preventing neurodegenerative diseases by counteracting oxidative stress and maintaining cellular integrity. Overall, our report recommends that further research is needed to optimize dosages and understand their long-term benefits.},
}

@article {pmid40198473,
year = {2025},
author = {Seok, HY},
title = {Critical issues in the use of edaravone for the treatment of amyotrophic lateral sclerosis.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {},
number = {},
pages = {},
pmid = {40198473},
issn = {1590-3478},
abstract = {Edaravone, along with riluzole, is a key treatment for amyotrophic lateral sclerosis (ALS), with evidence supporting its efficacy in slowing disease progression, particularly in patients with early-stage ALS. Despite its approval and increasing clinical use, several critical questions about its use remain unanswered: Can edaravone be effective as monotherapy? Is it beneficial for patients who fall outside the inclusion criteria of pivotal trials? What is the optimal duration of treatment as ALS progresses? In addition, does edaravone provide clinical benefit to patients with familial ALS? Answering these questions is essential to optimize the use of edaravone in clinical practice and to further our understanding of its role in the treatment of ALS. This review synthesizes the current evidence to address these questions and identifies areas that require further investigation.},
}

@article {pmid40196899,
year = {2025},
author = {Li, S and Pandat, T and Chi, B and Moon, D and Mas, M},
title = {Management Approaches to Spastic Gait Disorders.},
journal = {Muscle & nerve},
volume = {},
number = {},
pages = {},
doi = {10.1002/mus.28402},
pmid = {40196899},
issn = {1097-4598},
abstract = {Spastic gait presents clinically as the net mechanical consequence of neurological impairments of spasticity, weakness, and abnormal synergies and their interactions with the ground reaction force in patients with upper motor neuron syndromes and with some neuromuscular diseases. It is critical to differentiate whether the primary problem is weakness or spasticity, thus better understanding different phenotypes of spastic gait disorders. Pelvic girdle abnormality plays a pivotal role in determining the clinical presentation of gait disorders, since it determines the body vector and compensatory kinetic chain reactions in the knee and ankle joints. Knee joint abnormality can be a mechanical compensation for hip and/or ankle and foot abnormality. Diagnostic nerve blocks and instrumented gait analysis may be needed for diagnosing the underlying problems and developing an individualized plan of care. A wide spectrum of treatment options has been used to manage spastic gait disorders. Some are in early and investigational stages, such as neuromodulation modalities, while others are well-developed, such as therapeutic exercise, ankle-foot orthoses, botulinum toxin treatment, and surgical interventions. Physicians and other healthcare providers who manage spastic gait disorders should be familiar with these treatment options and should employ appropriate interventions concurrently rather than serially. The most effective treatments can be selected based on careful evaluation, inputs from patients, family, and therapists, along with appropriate goal setting. Treatment plans need to be re-evaluated for effectiveness, relevance, and in concordance with disease progress. This is particularly important for patients with progressive neuromuscular diseases such as amyotrophic lateral sclerosis.},
}

@article {pmid40192904,
year = {2025},
author = {Kodirov, SA},
title = {Comparison of Superoxide Dismutase Activity at the Cell, Organ, and Whole-Body Levels.},
journal = {Cell biochemistry and biophysics},
volume = {},
number = {},
pages = {},
pmid = {40192904},
issn = {1559-0283},
abstract = {Superoxide dismutase (SOD) can be considered an antitoxic metalloenzyme that facilitates the production of oxygen and hydrogen peroxide from superoxide anions. Four classes have been identified depending on selective binding of metals, namely Cu,Zn-SOD, Fe-SOD, Mn-SOD, and Ni-SOD. The established isoforms are SOD1, SOD2, and SOD3 in various cells and tissues of eukaryotes. The relatively newer type Ni-SOD binds nickel and is observed in bacteria, including the genus Streptomyces. The Fe-SOD and Mn-SOD are also present in bacteria. Cu,Zn superoxide dismutase (SOD1) activity correlates with various pathophysiological states of organs. SOD2 binds manganese (Mn) and is located in the mitochondria. The SOD3, similar to the SOD1, binds copper and zinc, which are also expressed in the brain. The assay relies on several methods, including the enzyme activities, expression, field potential, and patch-clamp electrophysiology. The effects of SOD activity are emphasized at organ and whole-body levels depending on animal models. The antioxidant properties and behavior of SOD are compared based on responses among females and males to diet and toxic substances. However, in humans with amyotrophic lateral sclerosis (ALS), the mean SOD activity in both erythrocytes and muscles was comparable to controls. The detailed comparisons between the catalase and SOD activities are one of the aspects of this review. Also, modulation of excitability and synaptic plasticity in neurons by SOD is highlighted.},
}

@article {pmid40189519,
year = {2025},
author = {Tseng, PT and Zeng, BY and Hsu, CW and Hung, CM and Carvalho, AF and Stubbs, B and Chen, YW and Chen, TY and Lei, WT and Chen, JJ and Su, KP and Shiue, YL and Liang, CS},
title = {The pharmacodynamics-based prophylactic benefits of GLP-1 receptor agonists and SGLT2 inhibitors on neurodegenerative diseases: evidence from a network meta-analysis.},
journal = {BMC medicine},
volume = {23},
number = {1},
pages = {197},
pmid = {40189519},
issn = {1741-7015},
mesh = {Humans ; *Sodium-Glucose Transporter 2 Inhibitors/therapeutic use/pharmacology ; *Neurodegenerative Diseases/prevention & control/drug therapy ; *Glucagon-Like Peptide-1 Receptor Agonists ; Randomized Controlled Trials as Topic ; Hypoglycemic Agents/pharmacology/therapeutic use ; },
abstract = {BACKGROUND: Glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose cotransporter 2 (SGLT2) inhibitors represent a new generation of antihyperglycemic agents that operate through mechanisms distinct from conventional diabetes treatments. Beyond their metabolic effects, these medications have demonstrated neuroprotective properties in preclinical studies. While clinical trials have explored their therapeutic potential in established neurodegenerative conditions, their role in disease prevention remains unclear. We conducted a network meta-analysis (NMA) to comprehensively evaluate the prophylactic benefits of these agents across multiple neurodegenerative diseases and identify the most promising preventive strategies.

METHODS: We systematically searched PubMed, Embase, ClinicalKey, Cochrane CENTRAL, ProQuest, ScienceDirect, Web of Science, and ClinicalTrials.gov through October 24th, 2024, for randomized controlled trials (RCTs) of GLP-1 receptor agonists or SGLT2 inhibitors. Our primary outcome was the incidence of seven major neurodegenerative diseases: Parkinson's disease, Alzheimer's disease, Lewy body dementia, multiple sclerosis, amyotrophic lateral sclerosis, frontotemporal dementia, and Huntington's disease. Secondary outcomes included safety profiles assessed through dropout rates. We performed a frequentist-based NMA and evaluated risk of bias with Risk of Bias tool. The main result of the primary outcome in the current study would be re-affirmed via sensitivity test with Bayesian-based NMA.

RESULTS: Our analysis encompassed 22 RCTs involving 138,282 participants (mean age 64.8 years, 36.4% female). Among all investigated medications, only dapagliflozin demonstrated significant prophylactic benefits, specifically in preventing Parkinson's disease (odds ratio = 0.28, 95% confidence intervals = 0.09 to 0.93) compared to controls. Neither GLP-1 receptor agonists nor other SGLT2 inhibitors showed significant preventive effects for any of the investigated neurodegenerative conditions. Drop-out rates were comparable across all treatments.

CONCLUSIONS: This comprehensive NMA reveals a novel and specific prophylactic effect of dapagliflozin against Parkinson's disease, representing a potential breakthrough in preventive neurology. The specificity of dapagliflozin's protective effect to Parkinson's disease might rely on its highly selective inhibition to SGLT2. These findings provide important direction for future research and could inform preventive strategies for populations at risk of Parkinson's disease.

TRIAL REGISTRATION: PROSPERO CRD42021252381.},
}

Humans
*Sodium-Glucose Transporter 2 Inhibitors/therapeutic use/pharmacology
*Neurodegenerative Diseases/prevention & control/drug therapy
*Glucagon-Like Peptide-1 Receptor Agonists
Randomized Controlled Trials as Topic
Hypoglycemic Agents/pharmacology/therapeutic use

@article {pmid40188980,
year = {2025},
author = {Chong, ZZ and Souayah, N},
title = {Pathogenic TDP-43 in amyotrophic lateral sclerosis.},
journal = {Drug discovery today},
volume = {30},
number = {5},
pages = {104351},
doi = {10.1016/j.drudis.2025.104351},
pmid = {40188980},
issn = {1878-5832},
abstract = {The aberrant expression of the transactive response DNA-binding protein of 43 kDa (TDP-43) has been closely associated with amyotrophic lateral sclerosis (ALS). Cytoplasmic inclusions containing TDP-43 can be found in the brain and spinal cord in up to 97% of ALS cases. Mutations in the TARDBP gene promote the nuclear export of TDP-43, increase cytoplasmic aggregation, and predispose TDP-43 to post-translational modifications. Cleavage of TDP-43 and the resulting C- and N-terminal fragments also contribute to the development of ALS. Cellularly, the resulting impairment of autophagy and mitochondria aggravates cellular damage and neurodegeneration. Given the contribution of pathogenic TDP-43 to the development of ALS, elucidating the mechanisms related to TDP-43 will facilitate finding therapeutic targets for the disease.},
}

@article {pmid40188375,
year = {2025},
author = {Prajapati, JL and Dhurandhar, Y and Singh, AP and Gupta, DK and Baghel, VS and Kushwaha, U and Namdeo, KP},
title = {Redox chemical delivery system: an innovative strategy for the treatment of neurodegenerative diseases.},
journal = {Expert opinion on drug delivery},
volume = {},
number = {},
pages = {1-18},
doi = {10.1080/17425247.2025.2489558},
pmid = {40188375},
issn = {1744-7593},
abstract = {INTRODUCTION: It is anticipated that the prevalence of illnesses affecting the central nervous system (CNS) will rise significantly due to longer lifespans and changing demography. Age-related decline in brain function and neuronal death are features of neurodegenerative disorders, such as Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis, which provide formidable treatment challenges. Because most therapeutic drugs cannot across the blood-brain barrier (BBB) to reach the brain, there are still few treatment alternatives available despite a great deal of research.

AREAS COVERED: This study explores the role of redox chemical delivery systems in CNS drug delivery and addresses challenges associated with neurodegenerative disease (ND). Redox Chemical Delivery System offers a promising approach to enhancing leveraging redox reactions that facilitate the transport of therapeutic agents across the BBB. Through the optimization of medication delivery pathways to the brain, this technology has the potential to greatly improve the treatment of ND.

EXPERT OPINION: As our understanding of the biological underpinnings of ND deepens, the potential for effective interventions increases. Refining drug delivery strategies, such as RCDS, is essential for advancing CNS therapies from research to clinical practice. These advancements could transform the management of ND, improving both treatment efficacy and patient outcomes.},
}

@article {pmid40187044,
year = {2025},
author = {Fu, Y and Zhang, J and Qin, R and Ren, Y and Zhou, T and Han, B and Liu, B},
title = {Activating autophagy to eliminate toxic protein aggregates with small molecules in neurodegenerative diseases.},
journal = {Pharmacological reviews},
volume = {77},
number = {3},
pages = {100053},
doi = {10.1016/j.pharmr.2025.100053},
pmid = {40187044},
issn = {1521-0081},
abstract = {Neurodegenerative diseases (NDs), such as Alzheimer disease, Parkinson disease, Huntington disease, amyotrophic lateral sclerosis, and frontotemporal dementia, are well known to pose formidable challenges for their treatment due to their intricate pathogenesis and substantial variability among patients, including differences in environmental exposures and genetic predispositions. One of the defining characteristics of NDs is widely reported to be the buildup of misfolded proteins. For example, Alzheimer disease is marked by amyloid beta and hyperphosphorylated Tau aggregates, whereas Parkinson disease exhibits α-synuclein aggregates. Amyotrophic lateral sclerosis and frontotemporal dementia exhibit TAR DNA-binding protein 43, superoxide dismutase 1, and fused-in sarcoma protein aggregates, and Huntington disease involves mutant huntingtin and polyglutamine aggregates. These misfolded proteins are the key biomarkers of NDs and also serve as potential therapeutic targets, as they can be addressed through autophagy, a process that removes excess cellular inclusions to maintain homeostasis. Various forms of autophagy, including macroautophagy, chaperone-mediated autophagy, and microautophagy, hold a promise in eliminating toxic proteins implicated in NDs. In this review, we focus on elucidating the regulatory connections between autophagy and toxic proteins in NDs, summarizing the cause of the aggregates, exploring their impact on autophagy mechanisms, and discussing how autophagy can regulate toxic protein aggregation. Moreover, we underscore the activation of autophagy as a potential therapeutic strategy across different NDs and small molecules capable of activating autophagy pathways, such as rapamycin targeting the mTOR pathway to clear α-synuclein and Sertraline targeting the AMPK/mTOR/RPS6KB1 pathway to clear Tau, to further illustrate their potential in NDs' therapeutic intervention. Together, these findings would provide new insights into current research trends and propose small-molecule drugs targeting autophagy as promising potential strategies for the future ND therapies. SIGNIFICANCE STATEMENT: This review provides an in-depth overview of the potential of activating autophagy to eliminate toxic protein aggregates in the treatment of neurodegenerative diseases. It also elucidates the fascinating interrelationships between toxic proteins and the process of autophagy of "chasing and escaping" phenomenon. Moreover, the review further discusses the progress utilizing small molecules to activate autophagy to improve the efficacy of therapies for neurodegenerative diseases by removing toxic protein aggregates.},
}

@article {pmid40185982,
year = {2025},
author = {Cummings, JL and Teunissen, CE and Fiske, BK and Le Ber, I and Wildsmith, KR and Schöll, M and Dunn, B and Scheltens, P},
title = {Biomarker-guided decision making in clinical drug development for neurodegenerative disorders.},
journal = {Nature reviews. Drug discovery},
volume = {},
number = {},
pages = {},
pmid = {40185982},
issn = {1474-1784},
abstract = {Neurodegenerative disorders are characterized by complex neurobiological changes that are reflected in biomarker alterations detectable in blood, cerebrospinal fluid (CSF) and with brain imaging. As accessible proxies for processes that are difficult to measure, biomarkers are tools that hold increasingly important roles in drug development and clinical trial decision making. In the past few years, biomarkers have been the basis for accelerated approval of new therapies for Alzheimer disease and amyotrophic lateral sclerosis as surrogate end points reasonably likely to predict clinical benefit.Blood-based biomarkers are emerging for Alzheimer disease and other neurodegenerative disorders (for example, Parkinson disease, frontotemporal dementia), and some biomarkers may be informative across multiple disease states. Collection of CSF provides access to biomarkers not available in plasma, including markers of synaptic dysfunction and neuroinflammation. Molecular imaging is identifying an increasing array of targets, including amyloid plaques, neurofibrillary tangles, inflammation, mitochondrial dysfunction and synaptic density. In this Review, we consider how biomarkers can be implemented in clinical trials depending on their context of use, including providing information on disease risk and/or susceptibility, diagnosis, prognosis, pharmacodynamic outcomes, monitoring, prediction of response to therapy and safety. Informed choice of increasingly available biomarkers and rational deployment in clinical trials support drug development decision making and de-risk the drug development process for neurodegenerative disorders.},
}

@article {pmid40185536,
year = {2025},
author = {Uzgiris, AJ and Ladic, LA and Pfister, SX},
title = {Advances in neurofilament light chain analysis.},
journal = {Advances in clinical chemistry},
volume = {126},
number = {},
pages = {31-71},
doi = {10.1016/bs.acc.2025.01.006},
pmid = {40185536},
issn = {2162-9471},
mesh = {*Neurofilament Proteins/analysis ; Humans ; Biomarkers/analysis ; *Nervous System Diseases/diagnosis/metabolism ; },
abstract = {This chapter provides a comprehensive summary of clinical laboratory testing for neurofilament light chain (NfL) in neurologic disease. A primer on the NfL structure and function is presented with its potential use as a biomarker. The most widely utilized methods for NfL in biologic samples are highlighted and examined. Limitations of current knowledge are considered, as are outstanding questions related to dissemination and standardization of testing. Herein we focus on methods available today and those in development for clinical use. In the final section, a broad vision is presented of how NfL may be utilized in the future to improve diagnosis and treatment of neurologic diseases as well as for maintaining health.},
}

*Neurofilament Proteins/analysis
Humans
Biomarkers/analysis
*Nervous System Diseases/diagnosis/metabolism

@article {pmid40184864,
year = {2025},
author = {Deloncle, R and Guillard, O and Pineau, A},
title = {Copper in human health: From COVID 19 to neurodegenerative diseases.},
journal = {Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS)},
volume = {89},
number = {},
pages = {127636},
doi = {10.1016/j.jtemb.2025.127636},
pmid = {40184864},
issn = {1878-3252},
abstract = {Copper (Cu) exists in two oxidation states Cu+I and Cu+II yielding formation of enzymes involved in biological processes. In higher concentrations, by oxidative process and ROS production, Cu is toxic towards plants, humans and animals livers as observed in Wilson disease or sheep scrapie. Fighting according to the Fenton reaction against bacteria and viruses, has been proposed as a mean of combatting nosocomial diseases and complementary to COVID19 vaccination. In humans, Cu is stocked in liver, muscle or bound to brain protein as ß-APP, tau-protein, α-synuclein, ubiquitin or prion which present antioxidant properties when Cu-bonded. In abnormal ß-sheet conformation, they can trigger neurodegenerative diseases such as Alzheimer(AD), Parkinson(PD) and ALS. In these diseases, blood copper increase correlated with brain copper decrease has been described. In AD, abnormal D-serine has been detected in blood and cerebrospinal fluid. D-glutamate and D-alanine blood levels have been found in AD and could also be controlled with Cu and ceruloplasmin in a possible disease screening test. This abnormal D-conformation might result from epimerization of physiologically L-conformation brain peptides into protease-resistant D-enantiomers. This has previously been experimentally demonstrated for Bovine Spongiform Encephalopathy in a free Cu reductive medium with UV-induced free radicals. The Cu brain protective effect against free radicals was restored with cupric addition in oxidizing medium. Cupric supplementation in the brain, might restore Cu protection and slow down neurodegenerative processes. To lower side effects, Cu amino-acid complexes able to cross the blood brain barrier might be suggested for a Cu transfer to the brain.},
}

@article {pmid40181198,
year = {2025},
author = {Manolopoulos, A and Yao, PJ and Kapogiannis, D},
title = {Extracellular vesicles: translational research and applications in neurology.},
journal = {Nature reviews. Neurology},
volume = {},
number = {},
pages = {},
pmid = {40181198},
issn = {1759-4766},
abstract = {Over the past few decades, extensive basic, translational and clinical research has been devoted to deciphering the physiological and pathogenic roles of extracellular vesicles (EVs) in the nervous system. The presence of brain cell-derived EVs in the blood, carrying diverse cargoes, has enabled the development of predictive, diagnostic, prognostic, disease-monitoring and treatment-response biomarkers for various neurological disorders. In this Review, we consider how EV biomarkers can bring us closer to understanding the complex pathogenesis of neurological disorders such as Alzheimer disease, Parkinson disease, stroke, traumatic brain injury, amyotrophic lateral sclerosis and multiple sclerosis. We describe how translational research on EVs might unfold bidirectionally, proceeding from basic to clinical studies but also in the opposite direction, with biomarker findings in the clinic leading to novel hypotheses that can be tested in the laboratory. We demonstrate the potential value of EVs across all stages of the therapeutic development pipeline, from identifying therapeutic targets to the use of EVs as reporters in model systems and biomarkers in clinical research. Finally, we discuss how the cargo and physicochemical properties of naturally occurring and custom-engineered EVs can be leveraged as novel treatments and vehicles for drug delivery, potentially revolutionizing neurotherapeutics.},
}

@article {pmid40180687,
year = {2025},
author = {Ms, S and Banerjee, S and D'Mello, SR and Dastidar, SG},
title = {Amyotrophic Lateral Sclerosis: Focus on Cytoplasmic Trafficking and Proteostasis.},
journal = {Molecular neurobiology},
volume = {},
number = {},
pages = {},
pmid = {40180687},
issn = {1559-1182},
support = {SAN No: 102/IFD/SAN/2549/2019-20//DBT RLS/ ; SAN No: 102/IFD/SAN/2549/2019-20//DBT RLS/ ; CRG/2022/005004//Science and Engineering Research Board/ ; CRG/2022/005004//Science and Engineering Research Board/ ; LBRN//Louisiana Biomedical Research Network/ ; IIRPIG-2023-0001508//Indian Council of Medical Research/ ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive and fatal motor neuron disease characterized by the pathological loss of upper and lower motor neurons. Whereas most ALS cases are caused by a combination of environmental factors and genetic susceptibility, in a relatively small proportion of cases, the disorder results from mutations in genes that are inherited. Defects in several different cellular mechanisms and processes contribute to the selective loss of motor neurons (MNs) in ALS. Prominent among these is the accumulation of aggregates of misfolded proteins or peptides which are toxic to motor neurons. These accumulating aggregates stress the ability of the endoplasmic reticulum (ER) to function normally, cause defects in the transport of proteins between the ER and Golgi, and impair the transport of RNA, proteins, and organelles, such as mitochondria, within axons and dendrites, all of which contribute to the degeneration of MNs. Although dysfunction of a variety of cellular processes combines towards the pathogenesis of ALS, in this review, we focus on recent advances concerning the involvement of defective ER stress, vesicular transport between the ER and Golgi, and axonal transport.},
}

@article {pmid40178484,
year = {2025},
author = {Gao, Y and Lu, Y and Chen, R and Zhao, S and Liu, J and Zhang, S and Bai, X and Zhang, J},
title = {Skin pathology in ALS: Diagnostic implications and biomarker potential.},
journal = {Biomolecules & biomedicine},
volume = {},
number = {},
pages = {},
doi = {10.17305/bb.2025.12100},
pmid = {40178484},
issn = {2831-090X},
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the loss of motor neurons in the spinal cord and brain, resulting in motor deficits and muscle atrophy. Approximately 5-10% of ALS patients are familial (fALS), while the rest are sporadic (sALS). Currently, early diagnosis of ALS cannot be achieved based on clinical manifestations and electromyography due to the lack of effective and easily available biomarkers. The skin and central nervous system (CNS) share the same embryonic origin. Several skin biomarkers have been found in many neurodegenerative diseases, such as abnormal deposition of pathological α-synuclein (α-Syn) in Parkinson's disease. Thus, molecular changes in the skin associated with ALS-specific pathological events could readily be detected and become biomarkers for ALS through skin testing. Here, we summarize the literature on pathological changes in the skin of ALS patients and animal models, including structural abnormalities of the skin, reduced density of skin nerve fibers, abnormal protein aggregation, altered mitochondrial morphology and function, and dysregulation of skin inflammation, which may be useful for early diagnosis and monitoring of ALS progression.},
}

@article {pmid40169538,
year = {2025},
author = {Iyer, KA and Tenchov, R and Sasso, JM and Ralhan, K and Jotshi, J and Polshakov, D and Maind, A and Zhou, QA},
title = {Rare Diseases, Spotlighting Amyotrophic Lateral Sclerosis, Huntington's Disease, and Myasthenia Gravis: Insights from Landscape Analysis of Current Research.},
journal = {Biochemistry},
volume = {64},
number = {8},
pages = {1698-1719},
pmid = {40169538},
issn = {1520-4995},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/therapy/pathology/metabolism ; *Myasthenia Gravis/genetics/therapy/pathology/metabolism ; *Rare Diseases/genetics/therapy ; *Huntington Disease/genetics/therapy/pathology/metabolism ; Animals ; },
abstract = {Rare diseases are a diverse group of disorders that, despite each individual condition's rarity, collectively affect a significant portion of the global population. Currently approximately 10,000 rare diseases exist globally, with 80% of these diseases being identified as having genetic origins. In this Review, we examine data from the CAS Content Collection to summarize scientific progress in the area of rare diseases. We examine the publication landscape in the area in an effort to provide insights into current advances and developments. We then discuss the evolution of key concepts in the field, genetic associations, as well as the major technologies and development pipelines of rare disease treatments. We focus our attention on three specific rare diseases: (i) amyotrophic lateral sclerosis, a terminal neurodegenerative disease affecting the central nervous system resulting in progressive loss of motor neurons that control voluntary muscles; (ii) Huntington's disease, another terminal neurodegenerative disease that causes progressive degeneration of nerve cells in the brain, with a wide impact on a person's functional abilities; and (iii) myasthenia gravis, a chronic autoimmune synaptopathy leading to skeletal muscle weakness. While the pathogenesis of these rare diseases is being elucidated, there is neither a cure nor preventative treatment available, only symptomatic treatment. The objective of the paper is to provide a broad overview of the evolving landscape of current knowledge on rare diseases and specifically on the biology and genetics of the three spotlighted diseases, to outline challenges and evaluate growth opportunities, an aim to further efforts in solving the remaining challenges.},
}

Humans
*Amyotrophic Lateral Sclerosis/genetics/therapy/pathology/metabolism
*Myasthenia Gravis/genetics/therapy/pathology/metabolism
*Rare Diseases/genetics/therapy
*Huntington Disease/genetics/therapy/pathology/metabolism
Animals

@article {pmid40169452,
year = {2025},
author = {Hou, X and Jiang, J and Deng, M},
title = {Exploring epigenetic modifications as potential biomarkers and therapeutic targets in amyotrophic lateral sclerosis.},
journal = {Journal of neurology},
volume = {272},
number = {4},
pages = {304},
pmid = {40169452},
issn = {1432-1459},
support = {82273915//National Natural Science Foundation of China/ ; },
mesh = {*Amyotrophic Lateral Sclerosis/genetics/diagnosis ; Humans ; *Epigenesis, Genetic ; *Biomarkers/metabolism ; DNA Methylation ; Animals ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder and the most common motor neuron disease. Whole-genome sequencing has identified many novel ALS-associated genes, but genetics alone cannot fully explain the onset of ALS and an effective treatment is still lacking. Moreover, we need more biomarkers for accurate diagnosis and assessment of disease prognosis. Epigenetics, which includes DNA methylation and hydroxymethylation, histone modifications, chromatin remodeling, and non-coding RNAs, influences gene transcription and expression by affecting chromatin accessibility and transcription factor binding without altering genetic information. These processes play a role in the onset and progression of ALS. Epigenetic targets can serve as potential biomarkers and more importantly, the reversibility of epigenetic changes supports their potential role as versatile therapeutic targets in ALS. This review summarized the alterations in different epigenetic modulations in ALS. Additionally, given the close association between aberrant metabolic profiles characterized by hypoxia and high glycolytic metabolism in ALS and epigenetic changes, we also integrate epigenetics with metabolomics. Finally, we discuss the application of therapies based on epigenetic mechanisms in ALS. Our data integration helps to identify potential diagnostic and prognostic biomarkers and support the development of new effective therapies.},
}

*Amyotrophic Lateral Sclerosis/genetics/diagnosis
Humans
*Epigenesis, Genetic
*Biomarkers/metabolism
DNA Methylation
Animals

@article {pmid40163151,
year = {2025},
author = {Wadan, AS and Shaaban, AH and El-Sadek, MZ and Mostafa, SA and Moshref, AS and El-Hussein, A and Ellakwa, DE and Mehanny, SS},
title = {Mitochondrial-based therapies for neurodegenerative diseases: a review of the current literature.},
journal = {Naunyn-Schmiedeberg's archives of pharmacology},
volume = {},
number = {},
pages = {},
pmid = {40163151},
issn = {1432-1912},
abstract = {Neurodegenerative disorders present significant challenges to modern medicine because of their complex etiology, pathogenesis, and progressive nature, which complicate practical treatment approaches. Mitochondrial dysfunction is an important contributor to the pathophysiology of various neurodegenerative illnesses, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). This review paper examines the current literature highlighting the multifaceted functions of mitochondria, including energy production, calcium signaling, apoptosis regulation, mitochondrial biogenesis, mitochondrial dynamics, axonal transport, endoplasmic reticulum-mitochondrial interactions, mitophagy, mitochondrial proteostasis, and their crucial involvement in neuronal health. The literature emphasizes the increasing recognition of mitochondrial dysfunction as a critical factor in the progression of neurodegenerative disorders, marking a shift from traditional symptom management to innovative mitochondrial-based therapies. By discussing mitochondrial mechanisms, including mitochondrial quality control (MQC) processes and the impact of oxidative stress, this review highlights the need for novel therapeutic strategies to restore mitochondrial function, protect neuronal connections and integrity, and slow disease progression. This comprehensive review aims to provide insights into potential interventions that could transform the treatment landscape for neurodegenerative diseases, addressing symptoms and underlying pathophysiological changes.},
}

@article {pmid40161216,
year = {2025},
author = {Scarcella, S and Brambilla, L and Quetti, L and Rizzuti, M and Melzi, V and Galli, N and Sali, L and Costamagna, G and Comi, GP and Corti, S and Gagliardi, D},
title = {Unveiling amyotrophic lateral sclerosis complexity: insights from proteomics, metabolomics and microbiomics.},
journal = {Brain communications},
volume = {7},
number = {2},
pages = {fcaf114},
pmid = {40161216},
issn = {2632-1297},
abstract = {Amyotrophic lateral sclerosis is the most common motor neuron disease and manifests as a clinically and genetically heterogeneous neurodegenerative disorder mainly affecting the motor systems. To date, despite promising results and accumulating knowledge on the pathomechanisms of amyotrophic lateral sclerosis, a specific disease-modifying treatment is still not available. In vitro and in vivo disease models coupled with multiomics techniques have helped elucidate the pathomechanisms underlying this disease. In particular, omics approaches are powerful tools for identifying new potential disease biomarkers that may be particularly useful for diagnosis, prognosis and assessment of treatment response. In turn, these findings could support physicians in stratifying patients into clinically relevant subgroups for the identification of the best therapeutic targets. Here, we provide a comprehensive review of the most relevant literature highlighting the importance of proteomics approaches in determining the role of pathogenic misfolded/aggregated proteins and the molecular mechanisms involved in the pathogenesis and progression of amyotrophic lateral sclerosis. In addition, we explored new findings arising from metabolomic and lipidomic studies, which can aid to elucidate the intricate metabolic alterations underlying amyotrophic lateral sclerosis pathology. Moreover, we integrated these insights with microbiomics data, providing a thorough understanding of the interplay between metabolic dysregulation and microbial dynamics in disease progression. Indeed, a greater integration of these multiomics data could lead to a deeper understanding of disease mechanisms, supporting the development of specific therapies for amyotrophic lateral sclerosis.},
}

@article {pmid40160105,
year = {2025},
author = {Malloy, E and Corrie, S and Cushen-Brewster, N},
title = {What is the current state of the research literature examining the impact of the motor neurone disease journey on the couple's relationship? A scoping review.},
journal = {Palliative & supportive care},
volume = {23},
number = {},
pages = {e85},
doi = {10.1017/S1478951524002141},
pmid = {40160105},
issn = {1478-9523},
mesh = {Humans ; *Motor Neuron Disease/psychology/complications ; Spouses/psychology ; Interpersonal Relations ; Adaptation, Psychological ; Female ; },
abstract = {BACKGROUND: Motor neurone disease (MND) results in complex and disabling symptoms that give rise to significant and challenging care needs. While much of the care required is typically provided by the partner of the individual who has been diagnosed with MND, there are few studies that have investigated the impact of MND on the couple's relationship.

OBJECTIVES: To establish the current state of the research literature examining the impact of MND on the couple's relationship.

METHODS: A scoping review was undertaken with thematic analysis used to synthesize the data.

RESULTS: The scoping review identified 15 studies that were thematically analyzed to identify prominent themes. The following 5 themes were identified: adjusting to new roles; changes in communication and values; spouse well-being and health; and changes to social relationships and intimacy changes.

SIGNIFICANCE OF RESULTS: This scoping review highlighted the impact of the MND trajectory on the couple's relationship overall and on key areas of couple communication and functioning. These areas can be used to guide the development of interventions and services that are tailored to the needs of couple relationships. Further understanding of the factors impacting the couple's relationship on the MND journey and how to navigate these factors is critically warranted.},
}

Humans
*Motor Neuron Disease/psychology/complications
Spouses/psychology
Interpersonal Relations
Adaptation, Psychological
Female

@article {pmid40153582,
year = {2025},
author = {Norata, D and Capone, F and Motolese, F and Marano, M and Rossi, M and Calandrelli, R and Sacchetti, M and Mantelli, F and Di Lazzaro, V and Pilato, F},
title = {1953-2023. Seventy Years of the Nerve Growth Factor: A Potential Novel Treatment in Neurological Diseases?.},
journal = {Aging and disease},
volume = {},
number = {},
pages = {},
doi = {10.14336/AD.2024.0573},
pmid = {40153582},
issn = {2152-5250},
abstract = {Rita Levi-Montalcini's 1953 discovery of nerve growth factor (NGF) in mouse sarcoma tumors marked a groundbreaking moment in neuroscience. NGF, a key signaling molecule, became the first identified neurotrophic factor, influencing the growth, differentiation, and survival of neurons in both peripheral and central nervous systems. NGF and related neurotrophic factors hold therapeutic potential for various neurological disorders, such as Alzheimer's Disease, Parkinson's Disease, Huntington's Disease, amyotrophic lateral sclerosis, spinal cord injuries, neuropathies, traumatic brain injuries, and stroke. However, despite promising in vitro studies and animal models findings, NGF efficacy in patients remains unproven. Indeed, its use as a therapeutic agent faces challenges in delivery and clinical translation. This review delves into these challenges, exploring ongoing research on refined delivery methods, dosages, and safety profiles. Innovative strategies, including molecular mimicking, combination therapies, gene therapy, and coupling with neuromodulation techniques like transcranial magnetic stimulation and vagal nerve stimulation, are discussed. Incorporating nerve growth factor (NGF) into a comprehensive strategy may prove beneficial, particularly in non-neurodegenerative conditions such as stroke, trauma, and neuropathies. In these instances, NGF holds promise for promoting tissue regeneration and repair. Challenges persist in addressing the complexity of neurodegenerative pathologies for a combined therapeutic approach.},
}

@article {pmid40149536,
year = {2025},
author = {Kleinerova, J and Chipika, RH and Tan, EL and Yunusova, Y and Marchand-Pauvert, V and Kassubek, J and Pradat, PF and Bede, P},
title = {Sensory Dysfunction in ALS and Other Motor Neuron Diseases: Clinical Relevance, Histopathology, Neurophysiology, and Insights from Neuroimaging.},
journal = {Biomedicines},
volume = {13},
number = {3},
pages = {},
pmid = {40149536},
issn = {2227-9059},
support = {JPND-Cofund-2-2019-1 & HRB EIA-2017-019//HRB/ ; },
abstract = {Background: The clinical profiles of MNDs are dominated by inexorable motor decline, but subclinical proprioceptive, nociceptive and somatosensory deficits may also exacerbate mobility, dexterity, and bulbar function. While extra-motor pathology and frontotemporal involvement are widely recognised in motor neuron diseases (MNDs), reports of sensory involvement are conflicting. The potential contribution of sensory deficits to clinical disability is not firmly established and the spectrum of sensory manifestations is poorly characterised. Methods: A systematic review was conducted to examine the clinical, neuroimaging, electrophysiology and neuropathology evidence for sensory dysfunction in MND phenotypes. Results: In ALS, paraesthesia, pain, proprioceptive deficits and taste alterations are sporadically reported and there is also compelling electrophysiological, histological and imaging evidence of sensory network alterations. Gait impairment, impaired dexterity, and poor balance in ALS are likely to be multifactorial, with extrapyramidal, cerebellar, proprioceptive and vestibular deficits at play. Human imaging studies and animal models also confirm dorsal column-medial lemniscus pathway involvement as part of the disease process. Sensory symptoms are relatively common in spinal and bulbar muscular atrophy (SBMA) and Hereditary Spastic Paraplegia (HSP), but are inconsistently reported in primary lateral sclerosis (PLS) and in post-poliomyelitis syndrome (PPS). Conclusions: Establishing the prevalence and nature of sensory dysfunction across the spectrum of MNDs has a dual clinical and academic relevance. From a clinical perspective, subtle sensory deficits are likely to impact the disability profile and care needs of patients with MND. From an academic standpoint, sensory networks may be ideally suited to evaluate propagation patterns and the involvement of subcortical grey matter structures. Our review suggests that sensory dysfunction is an important albeit under-recognised facet of MND.},
}

@article {pmid40148057,
year = {2025},
author = {De Marchi, F and Spinelli, EG and Bendotti, C},
title = {Neuroglia in neurodegeneration: Amyotrophic lateral sclerosis and frontotemporal dementia.},
journal = {Handbook of clinical neurology},
volume = {210},
number = {},
pages = {45-67},
doi = {10.1016/B978-0-443-19102-2.00004-1},
pmid = {40148057},
issn = {0072-9752},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology ; *Frontotemporal Dementia/pathology ; *Neuroglia/pathology ; Animals ; },
abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are devastating neurodegenerative diseases sharing significant pathologic and genetic overlap, leading to consider these diseases as a continuum in the spectrum of their pathologic features. Although FTD compromises only specific brain districts, while ALS involves both the nervous system and the skeletal muscles, several neurocentric mechanisms are in common between ALS and FTD. Also, recent research has revealed the significant involvement of nonneuronal cells, particularly glial cells such as astrocytes, oligodendrocytes, microglia, and peripheral immune cells, in disease pathology. This chapter aims to provide an extensive overview of the current understanding of the role of glia in the onset and advancement of ALS and FTD, highlighting the recent implications in terms of prognosis and future treatment options.},
}

Humans
*Amyotrophic Lateral Sclerosis/pathology
*Frontotemporal Dementia/pathology
*Neuroglia/pathology
Animals

@article {pmid40143051,
year = {2025},
author = {Zou, Y and Zhang, J and Chen, L and Xu, Q and Yao, S and Chen, H},
title = {Targeting Neuroinflammation in Central Nervous System Diseases by Oral Delivery of Lipid Nanoparticles.},
journal = {Pharmaceutics},
volume = {17},
number = {3},
pages = {},
pmid = {40143051},
issn = {1999-4923},
support = {82100892//Hong Chen/ ; 82300929//Jing Zhang/ ; },
abstract = {Neuroinflammation within the central nervous system (CNS) is a primary characteristic of CNS diseases, such as Parkinson's disease, Alzheimer's disease (AD), amyotrophic lateral sclerosis, and mental disorders. The excessive activation of immune cells results in the massive release of pro-inflammatory cytokines, which subsequently induce neuronal death and accelerate the progression of neurodegeneration. Therefore, mitigating excessive neuroinflammation has emerged as a promising strategy for the treatment of CNS diseases. Despite advancements in drug discovery and the development of novel therapeutics, the effective delivery of these agents to the CNS remains a serious challenge due to the restrictive nature of the blood-brain barrier (BBB). This underscores the need to develop a novel drug delivery system. Recent studies have identified oral lipid nanoparticles (LNPs) as a promising approach to efficiently deliver drugs across the BBB and treat neurological diseases. This review aims to comprehensively summarize the recent advancements in the development of LNPs designed for the controlled delivery and therapeutic modulation of CNS diseases through oral administration. Furthermore, this review addresses the mechanisms by which these LNPs overcome biological barriers and evaluate their clinical implications and therapeutic efficacy in the context of oral drug delivery systems. Specifically, it focuses on LNP formulations that facilitate oral administration, exploring their potential to enhance bioavailability, improve targeting precision, and alleviate or manage the symptoms associated with a range of CNS diseases.},
}

@article {pmid40141996,
year = {2025},
author = {Kodama, TS and Furuita, K and Kojima, C},
title = {Beyond Static Tethering at Membrane Contact Sites: Structural Dynamics and Functional Implications of VAP Proteins.},
journal = {Molecules (Basel, Switzerland)},
volume = {30},
number = {6},
pages = {},
pmid = {40141996},
issn = {1420-3049},
support = {JP22H05536, JP22K19184, JP23H02416, and JP23K18030//Ministry of Education, Culture, Sports, Science and Technology/ ; NMR Platform//Ministry of Education, Culture, Sports, Science and Technology/ ; CR-24-05//Institute for Protein Research, Osaka University/ ; JP24ama121001//Japan Agency for Medical Research and Development/ ; },
mesh = {Humans ; *Vesicular Transport Proteins/chemistry/metabolism ; Cell Membrane/metabolism/chemistry ; Animals ; Protein Conformation ; Phylogeny ; },
abstract = {The membranes surrounding the eukaryotic cell and its organelles are continuously invaginating, budding, and undergoing membrane fusion-fission events, which enable them to perform functions not found in prokaryotic cells. In addition, organelles come into close contact with each other at membrane contact sites (MCSs), which involve many types of proteins, and which regulate the signaling and transport of various molecules. Vesicle-associated membrane protein (VAMP)-associated protein (VAP) is an important factor involved in the tethering and contact of various organelles at MCSs in almost all eukaryotes and has attracted attention for its association with various diseases, mainly neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). However, the detailed mechanism of its functional expression remains unclear. In this review, we quantitatively discuss the structural dynamics of the entire molecule, including intrinsically disordered regions and intramolecular and intermolecular interactions, focusing on the vertebrate VAP paralogs VAPA and VAPB. Molecular phylogenetic and biophysical considerations are the basis of the work.},
}

Humans
*Vesicular Transport Proteins/chemistry/metabolism
Cell Membrane/metabolism/chemistry
Animals
Protein Conformation
Phylogeny

@article {pmid40141987,
year = {2025},
author = {Russo, A and Putaggio, S and Tellone, E and Calderaro, A and Cirmi, S and Laganà, G and Ficarra, S and Barreca, D and Patanè, GT},
title = {Emerging Ferroptosis Involvement in Amyotrophic Lateral Sclerosis Pathogenesis: Neuroprotective Activity of Polyphenols.},
journal = {Molecules (Basel, Switzerland)},
volume = {30},
number = {6},
pages = {},
pmid = {40141987},
issn = {1420-3049},
mesh = {*Ferroptosis/drug effects ; Humans ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/drug therapy/genetics ; *Polyphenols/pharmacology ; *Neuroprotective Agents/pharmacology/therapeutic use ; Animals ; Reactive Oxygen Species/metabolism ; Lipid Peroxidation/drug effects ; Oxidative Stress/drug effects ; Mitochondria/metabolism/drug effects ; Iron/metabolism ; },
abstract = {Neurodegenerative diseases are a group of diseases that share common features, such as the generation of misfolded protein deposits and increased oxidative stress. Among them, amyotrophic lateral sclerosis (ALS), whose pathogenesis is still not entirely clear, is a complex neurodegenerative disease linked both to gene mutations affecting different proteins, such as superoxide dismutase 1, Tar DNA binding protein 43, Chromosome 9 open frame 72, and Fused in Sarcoma, and to altered iron homeostasis, mitochondrial dysfunction, oxidative stress, and impaired glutamate metabolism. The purpose of this review is to highlight the molecular targets common to ALS and ferroptosis. Indeed, many pathways implicated in the disease are hallmarks of ferroptosis, a recently discovered type of iron-dependent programmed cell death characterized by increased reactive oxygen species (ROS) and lipid peroxidation. Iron accumulation results in mitochondrial dysfunction and increased levels of ROS, lipid peroxidation, and ferroptosis triggers; in addition, the inhibition of the Xc[-] system results in reduced cystine levels and glutamate accumulation, leading to excitotoxicity and the inhibition of GPx4 synthesis. These results highlight the potential involvement of ferroptosis in ALS, providing new molecular and biochemical targets that could be exploited in the treatment of the disease using polyphenols.},
}

*Ferroptosis/drug effects
Humans
*Amyotrophic Lateral Sclerosis/metabolism/pathology/drug therapy/genetics
*Polyphenols/pharmacology
*Neuroprotective Agents/pharmacology/therapeutic use
Animals
Reactive Oxygen Species/metabolism
Lipid Peroxidation/drug effects
Oxidative Stress/drug effects
Mitochondria/metabolism/drug effects
Iron/metabolism

@article {pmid40141149,
year = {2025},
author = {Zheng, MY and Luo, LZ},
title = {The Role of IL-17A in Mediating Inflammatory Responses and Progression of Neurodegenerative Diseases.},
journal = {International journal of molecular sciences},
volume = {26},
number = {6},
pages = {},
pmid = {40141149},
issn = {1422-0067},
support = {No. 2023D022//the Fujian Provincial Natural Science Foundation/ ; No. 3502Z202473076//the Science and Technology Program of Xiamen City/ ; No. 2019-WJ-30//the Fujian Province Health Education Joint Research Project/ ; },
mesh = {Humans ; *Interleukin-17/metabolism/immunology ; *Neurodegenerative Diseases/metabolism/immunology/pathology ; Animals ; Inflammation/metabolism/immunology/pathology ; Receptors, Interleukin-17/metabolism ; Signal Transduction ; Disease Progression ; Blood-Brain Barrier/metabolism/immunology ; },
abstract = {IL-17A has been implicated as a critical pro-inflammatory cytokine in the pathogenesis of autoimmune and neurodegenerative disorders. Emerging evidence indicates its capacity to activate microglial cells and astrocytes, subsequently inducing the production of inflammatory mediators that exacerbate neuronal injury and functional impairment. Clinical observations have revealed a demonstrated association between IL-17A concentrations and blood-brain barrier (BBB) dysfunction, creating a pathological feedback loop that amplifies neuro-inflammatory responses. Recent advances highlight the cytokine's critical involvement in neurodegenerative disorders through multiple molecular pathways. Therapeutic interventions utilizing monoclonal antibodies (mAbs) against IL-17A or its cognate receptor (IL-17R) have shown promising clinical potential. This review systematically examines the IL-17A-mediated neuro-inflammatory cascades; the mechanistic contributions to neurodegenerative pathology in the established disease models including multiple sclerosis, Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis; and current therapeutic strategies targeting the IL-17A signaling pathways. The analysis provides novel perspectives on optimizing cytokine-directed therapies while identifying the key challenges and research priorities for translational applications in neurodegeneration.},
}

Humans
*Interleukin-17/metabolism/immunology
*Neurodegenerative Diseases/metabolism/immunology/pathology
Animals
Inflammation/metabolism/immunology/pathology
Receptors, Interleukin-17/metabolism
Signal Transduction
Disease Progression
Blood-Brain Barrier/metabolism/immunology