@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

@article {pmid40138119,
year = {2025},
author = {Ali, N and Sayeed, U and Shahid, SMA and Akhtar, S and Khan, MKA},
title = {Molecular mechanisms and biomarkers in neurodegenerative disorders: a comprehensive review.},
journal = {Molecular biology reports},
volume = {52},
number = {1},
pages = {337},
pmid = {40138119},
issn = {1573-4978},
mesh = {Humans ; *Biomarkers/metabolism ; *Neurodegenerative Diseases/diagnosis/metabolism/cerebrospinal fluid ; Amyloid beta-Peptides/metabolism/cerebrospinal fluid ; tau Proteins/metabolism/cerebrospinal fluid ; Parkinson Disease/diagnosis/metabolism/genetics/cerebrospinal fluid ; alpha-Synuclein/metabolism ; Alzheimer Disease/diagnosis/metabolism/genetics ; Amyotrophic Lateral Sclerosis/metabolism/diagnosis/genetics/cerebrospinal fluid ; Huntington Disease/diagnosis/metabolism/genetics ; Positron-Emission Tomography/methods ; },
abstract = {Neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic Lateral Sclerosis (ALS), and Huntington's disease (HD), are significant global health challenges, owing to their profound impact on cognitive, motor, and behavioral functions. The etiology and progression of these disorders are influenced by a complex interplay of environmental factors and genetic predispositions with specific genetic markers, such as mutations in the APOE and HTT genes, which play pivotal roles. Current therapeutic interventions predominantly focus on symptom management; however, emerging strategies, including gene therapies, anti-amyloid agents, and neuroprotective approaches, are designed to directly target the underlying disease mechanisms. Advances in biomarker discovery and imaging methodologies have emerged as essential tools for early diagnosis and monitoring of therapeutic efficacy in these disorders. In the context of AD, cerebrospinal fluid (CSF) amyloid-beta (Aβ) and tau levels, along with positron emission tomography (PET) imaging, are well-established biomarkers. Similarly, CSF alpha-synuclein and dopamine transporter (DAT) imaging have been employed as diagnostic tools for PD. Moreover, emerging biomarkers, such as blood-based tau and the Aβ42/40 ratio for AD, as well as the neurofilament light chain (NfL) for ALS and PD, hold promise for enhancing early diagnostic accuracy and facilitating the longitudinal assessment of disease progression. This study comprehensively examined the molecular mechanisms underlying these neurodegenerative disorders, focusing on amyloid-beta plaque deposition and tau protein aggregation in AD, alpha-synuclein misfolding in PD, and aberrant protein aggregation in ALS and HD, thereby contributing to a deeper understanding of the pathophysiological basis of these disorders.},
}

Humans
*Biomarkers/metabolism
*Neurodegenerative Diseases/diagnosis/metabolism/cerebrospinal fluid
Amyloid beta-Peptides/metabolism/cerebrospinal fluid
tau Proteins/metabolism/cerebrospinal fluid
Parkinson Disease/diagnosis/metabolism/genetics/cerebrospinal fluid
alpha-Synuclein/metabolism
Alzheimer Disease/diagnosis/metabolism/genetics
Amyotrophic Lateral Sclerosis/metabolism/diagnosis/genetics/cerebrospinal fluid
Huntington Disease/diagnosis/metabolism/genetics
Positron-Emission Tomography/methods

@article {pmid40137505,
year = {2025},
author = {Calderón-Garcidueñas, L and González-Maciel, A and Reynoso-Robles, R and Cejudo-Ruiz, FR and Silva-Pereyra, HG and Gorzalski, A and Torres-Jardón, R},
title = {Alzheimer's, Parkinson's, Frontotemporal Lobar Degeneration, and Amyotrophic Lateral Sclerosis Start in Pediatric Ages: Ultrafine Particulate Matter and Industrial Nanoparticles Are Key in the Early-Onset Neurodegeneration: Time to Invest in Preventive Medicine.},
journal = {Toxics},
volume = {13},
number = {3},
pages = {},
pmid = {40137505},
issn = {2305-6304},
abstract = {Billions of people are exposed to fine particulate matter (PM2.5) levels above the USEPA's annual standard of 9 μg/m[3]. Common emission sources are anthropogenic, producing complex aerosolized toxins. Ultrafine particulate matter (UFPM) and industrial nanoparticles (NPs) have major detrimental effects on the brain, but the USA does not measure UFPM on a routine basis. This review focuses on the development and progression of common neurodegenerative diseases, as diagnosed through neuropathology, among young residents in Metropolitan Mexico City (MMC). MMC is one of the most polluted megacities in the world, with a population of 22 million residents, many of whom are unaware of the brain effects caused by their polluted atmosphere. Fatal neurodegenerative diseases (such as Alzheimer's and Parkinson's) that begin in childhood in populations living in air polluted environments are preventable. We conclude that UFPM/NPs are capable of disrupting neural homeostasis and give rise to relentless neurodegenerative processes throughout the entire life of the highly exposed population in MMC. The paradigm of reaching old age to have neurodegeneration is no longer supported. Neurodegenerative changes start early in pediatric ages and are irreversible. It is time to invest in preventive medicine.},
}

@article {pmid40137226,
year = {2025},
author = {Stella, R and Bertoli, A and Lopreiato, R and Peggion, C},
title = {A Twist in Yeast: New Perspectives for Studying TDP-43 Proteinopathies in S. cerevisiae.},
journal = {Journal of fungi (Basel, Switzerland)},
volume = {11},
number = {3},
pages = {},
pmid = {40137226},
issn = {2309-608X},
abstract = {TAR DNA-binding protein 43 kDa (TDP-43) proteinopathies are a group of neurodegenerative diseases (NDs) characterized by the abnormal accumulation of the TDP-43 protein in neurons and glial cells. These proteinopathies are associated with several NDs, including amyotrophic lateral sclerosis, frontotemporal lobar degeneration, and some forms of Alzheimer's disease. Yeast models have proven valuable in ND research due to their simplicity, genetic tractability, and the conservation of many cellular processes shared with higher eukaryotes. For several decades, Saccharomyces cerevisiae has been used as a model organism to study the behavior and toxicity of TDP-43, facilitating the identification of genes and pathways that either exacerbate or mitigate its toxic effects. This review will discuss evidence showing that yeast models of TDP-43 exhibit defects in proteostasis, mitochondrial function, autophagy, and RNA metabolism, which are key features of TDP-43-related NDs. Additionally, we will explore how modulating proteins involved in these processes reduce TDP-43 toxicity, aiding in restoring normal TDP-43 function or preventing its pathological aggregation. These findings highlight potential therapeutic targets for the treatment of TDP-43-related diseases.},
}

@article {pmid40136670,
year = {2025},
author = {Bond, S and Saxena, S and Sierra-Delgado, JA},
title = {Microglia in ALS: Insights into Mechanisms and Therapeutic Potential.},
journal = {Cells},
volume = {14},
number = {6},
pages = {},
pmid = {40136670},
issn = {2073-4409},
support = {//Rare Village/ ; //Radala Foundation/ ; //University of Missouri- Columbia, School of Medicine/ ; },
mesh = {*Amyotrophic Lateral Sclerosis/therapy/pathology/immunology ; Humans ; *Microglia/pathology/metabolism ; Animals ; Motor Neurons/pathology/metabolism ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the loss of motor neurons, leading to escalating muscle weakness, atrophy, and eventually paralysis. While neurons are the most visibly affected, emerging data highlight microglia-the brain's resident immune cells-as key contributors to disease onset and progression. Rather than existing in a simple beneficial or harmful duality, microglia can adopt multiple functional states shaped by internal and external factors, including those in ALS. Collectively, these disease-specific forms are called disease-associated microglia (DAM). Research using rodent models, patient-derived cells, and human postmortem tissue shows that microglia can transition into DAM phenotypes, driving inflammation and neuronal injury. However, these cells can also fulfill protective roles under certain conditions, revealing their adaptable nature. This review explores recent discoveries regarding the multifaceted behavior of microglia in ALS, highlights important findings that link these immune cells to motor neuron deterioration, and discusses emerging therapies-some already used in clinical trials-that aim to recalibrate microglial functions and potentially slow disease progression.},
}

*Amyotrophic Lateral Sclerosis/therapy/pathology/immunology
Humans
*Microglia/pathology/metabolism
Animals
Motor Neurons/pathology/metabolism

@article {pmid40136528,
year = {2025},
author = {Chen, X and Wang, Y and Zhang, Y and Li, X and Zhang, L and Gao, S and Zhang, C},
title = {Neural Excitatory/Inhibitory Imbalance in Motor Aging: From Genetic Mechanisms to Therapeutic Challenges.},
journal = {Biology},
volume = {14},
number = {3},
pages = {},
pmid = {40136528},
issn = {2079-7737},
support = {C2406001//the Shenzhen Medical Research Fund/ ; 2024TJCR023//the Tongji Hospital High Quality Clinical Research Fund/ ; 32020103007//the Major International (Regional) Joint Research Project/ ; 2022YFA1206000//the National Key Research and Development Program of China/ ; 32371189, 32300984//the National Natural Science Foundation of China/ ; },
abstract = {Neural excitatory/inhibitory (E/I) imbalance plays a pivotal role in the aging process. However, despite its significant impact, the role of E/I imbalance in motor dysfunction and neurodegenerative diseases has not received sufficient attention. This review explores the mechanisms underlying motor aging through the lens of E/I balance, emphasizing genetic and molecular factors that contribute to this imbalance (such as SCN2A, CACNA1C, GABRB3, GRIN2A, SYT, BDNF…). Key regulatory genes, including REST, vps-34, and STXBP1, are examined for their roles in modulating synaptic activity and neuronal function during aging. With insights drawn from ALS, we discuss how disruptions in E/I balance contribute to the pathophysiology of age-related motor dysfunction. The genes discussed above exhibit a certain association with age-related motor neuron diseases (like ALS), a relationship that had not been previously recognized. Innovative genetic therapies, such as gene editing technology and optogenetic manipulation, are emerging as promising tools for restoring E/I balance, offering hope for ameliorating motor deficits in aging. This review explores the potential of these technologies to intervene in aging-related motor diseases, despite challenges in their direct application to human conditions.},
}

@article {pmid40132681,
year = {2025},
author = {Wang, Z and Yang, C and Wang, X and Lyu, W and Liao, H and Liu, X and Liu, H and Zhang, J and Shen, H and Zhang, L and Wang, H},
title = {Decoding stress granules dynamics: Implications for neurodegenerative disease.},
journal = {Progress in neurobiology},
volume = {248},
number = {},
pages = {102758},
doi = {10.1016/j.pneurobio.2025.102758},
pmid = {40132681},
issn = {1873-5118},
abstract = {Stress granules (SGs) are membrane-less cytoplasmic structures formed by cells in response to external stress, primarily composed of mRNA and proteins. The dynamic properties of their assembly, maintenance, and disassembly play crucial roles in cellular homeostasis. Recent studies have increasingly revealed that aberrations in SGs dynamics are closely related to the pathogenesis of various neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. This review summarizes the latest research progress on SGs dynamics in neurodegenerative diseases. It begins with an overview of the basic biological characteristics of SGs and their functions in neurons, followed by an in-depth exploration of the mechanisms and regulatory pathways of SGs dynamics. The review then summarizes potential therapeutic strategies targeting SGs dynamics abnormalities, particularly through small molecule drugs to modulate SGs formation and disassembly, aiming to delay or halt the progression of neurodegenerative diseases. The review also highlights the application prospects of these interventions in treating neurodegenerative diseases. Finally, the review introduces current techniques used to study SGs dynamics, discussing their advantages, limitations, and future development possibilities. This review aims to provide researchers with a comprehensive perspective to advance the understanding and clinical application of SGs dynamics in the field of neurodegenerative diseases.},
}

@article {pmid40131291,
year = {2025},
author = {Penn, J and McAleer, R and Ziegler, C and Cheskes, S and Nolan, B and von Vopelius-Feldt, J},
title = {Effectiveness of Prehospital Critical Care Scene Response for Major Trauma: A Systematic Review.},
journal = {Prehospital emergency care},
volume = {},
number = {},
pages = {1-14},
doi = {10.1080/10903127.2025.2483978},
pmid = {40131291},
issn = {1545-0066},
abstract = {OBJECTIVES: Major trauma is a leading cause of morbidity and mortality worldwide. It is unclear if the addition of a critical care response unit (CCRU) with capabilities comparable to hospital emergency departments might improve outcomes following major trauma, when added to Basic or Advanced Life Support (BLS/ALS) prehospital care. This systematic review describes the evidence for a CCRU scene response model for major trauma.

METHODS: We searched Medline (Ovid), Embase (Ovid), Cochrane Central Register of Controlled Trials (Ovid), CINAHL (EBSCOhost), Science Citation Index Expanded (Web of Science), Conference Proceedings Citation Index - Science (Web of Science), LILACS (Latin American and Caribbean Health Sciences Literature) for relevant publications from 2003 to 2024. We included any study that compared CCRU and BLS/ALS care at the scene of major trauma, reported patient-focused outcomes, and utilized statistical methods to reduce bias and confounding. The risk of bias was assessed by two independent reviewers, using the ROBINS-I tool. Based on our a priori knowledge of the literature, a narrative analysis was chosen. The review was prospectively registered (PROSPERO ID CRD42023490668).

RESULTS: The search yielded 5243 unique records, of which 26 retrospective cohort studies and one randomized controlled trial met inclusion criteria. Sample sizes ranged from 308 to 153,729 patients. Eighteen of the 27 included studies showed associations between CCRUs and improved survival following trauma, which appear to be more consistently found in more critically injured and adult patients, as well as those suffering traumatic cardiac arrest. The remaining nine studies showed no significant difference in outcomes between CCRU and BLS/ALS care. Most studies demonstrated critical or severe risks of bias.

CONCLUSIONS: Current evidence examining CCRU scene response for major trauma suggests potential benefits in severely injury patients but is limited by overall low quality. Further high-quality research is required to confirm the benefits from CCRU scene response for major trauma.},
}

@article {pmid40128823,
year = {2025},
author = {Zhang, W and Huang, C and Yao, H and Yang, S and Jiapaer, Z and Song, J and Wang, X},
title = {Retrotransposon: an insight into neurological disorders from perspectives of neurodevelopment and aging.},
journal = {Translational neurodegeneration},
volume = {14},
number = {1},
pages = {14},
pmid = {40128823},
issn = {2047-9158},
support = {2023TSYCCX0051//Tianshan Talent Training Program/ ; },
mesh = {Humans ; *Retroelements/genetics ; *Aging/genetics ; *Nervous System Diseases/genetics ; Animals ; },
abstract = {Neurological disorders present considerable challenges in diagnosis and treatment due to their complex and diverse etiology. Retrotransposons are a type of mobile genetic element that are increasingly revealed to play a role in these diseases. This review provides a detailed overview of recent developments in the study of retrotransposons in neurodevelopment, neuroaging, and neurological diseases. Retrotransposons, including long interspersed nuclear elements-1, Alu, SINE-VNTR-Alu, and endogenous retrovirus, play important regulatory roles in the development and aging of the nervous system. They have also been implicated in the pathological processes of several neurological diseases, including Alzheimer's disease, X-linked dystonia-parkinsonism, amyotrophic lateral sclerosis, autism spectrum disorder, and schizophrenia. Retrotransposons provide a new perspective for understanding the molecular mechanisms underlying neurological diseases and provide insights into diagnostic and therapeutic strategies of these diseases.},
}

Humans
*Retroelements/genetics
*Aging/genetics
*Nervous System Diseases/genetics
Animals

@article {pmid40122623,
year = {2025},
author = {Ghanizada, H and Nedergaard, M},
title = {The glymphatic system.},
journal = {Handbook of clinical neurology},
volume = {209},
number = {},
pages = {161-170},
doi = {10.1016/B978-0-443-19104-6.00006-1},
pmid = {40122623},
issn = {0072-9752},
mesh = {Humans ; *Glymphatic System ; Neurodegenerative Diseases/therapy ; Animals ; Brain ; },
abstract = {The glymphatic system, a brain-wide network-supporting cerebrospinal fluid (CSF) and interstitial fluid (ISF) exchange, is essential for removing metabolic waste from the brain. This system's proper functioning is crucial for maintaining neural health and preventing the accumulation of harmful substances that can lead to neurodegenerative diseases. This chapter explores the glymphatic system's mechanisms, its dysfunction in various neurologic disorders, and potential therapeutic strategies. Recent discoveries reveal the glymphatic system's involvement in aging, sleep, cerebral edema, and conditions, such as Alzheimer, Parkinson, Huntington diseases, amyotrophic lateral sclerosis, small vessel disease, hydrocephalus, migraine, stroke, traumatic brain injury, and psychiatric disorders, where impaired waste clearance contributes to disease pathogenesis. Moreover, therapeutic interventions targeting glymphatic dysfunction present promising avenues for mitigating the effects of neurodegenerative diseases. The chapter underscores the potential of integrating glymphatic research into broader clinical practices, offering new strategies for disease management and prevention.},
}

Humans
*Glymphatic System
Neurodegenerative Diseases/therapy
Animals
Brain

@article {pmid40122396,
year = {2025},
author = {Cao, Y and Xu, Y and Cao, M and Chen, N and Zeng, Q and Lai, MKP and Fan, D and Sethi, G and Cao, Y},
title = {Fluid-based biomarkers for neurodegenerative diseases.},
journal = {Ageing research reviews},
volume = {108},
number = {},
pages = {102739},
doi = {10.1016/j.arr.2025.102739},
pmid = {40122396},
issn = {1872-9649},
abstract = {Neurodegenerative diseases, such as Alzheimer's Disease (AD), Multiple Sclerosis (MS), Parkinson's Disease (PD), and Amyotrophic Lateral Sclerosis (ALS) are increasingly prevalent as global populations age. Fluid biomarkers, derived from cerebrospinal fluid (CSF), blood, saliva, urine, and exosomes, offer a promising solution for early diagnosis, prognosis, and disease monitoring. These biomarkers can reflect critical pathological processes like amyloid-beta (Aβ) deposition, tau protein hyperphosphorylation, α-syn misfolding, TDP-43 mislocalization and aggregation, and neuronal damage, enabling detection long before clinical symptoms emerge. Recent advances in blood-based biomarkers, particularly plasma Aβ, phosphorylated tau, and TDP-43, have shown diagnostic accuracy equivalent to CSF biomarkers, offering more accessible testing options. This review discusses the current challenges in fluid biomarker research, including variability, standardization, and sensitivity issues, and explores how combining multiple biomarkers with clinical symptoms improves diagnostic reliability. Ethical considerations, future directions involving extracellular vehicles (EVs), and the integration of artificial intelligence (AI) are also highlighted. Continued research efforts will be key to overcoming these obstacles, enabling fluid biomarkers to become crucial tools in personalized medicine for neurodegenerative diseases.},
}

@article {pmid40120962,
year = {2025},
author = {Zhang, X and Wang, J and Zhang, J and Jiang, C and Liu, X and Wang, S and Zhang, Z and Rastegar-Kashkooli, Y and Dialameh, F and Peng, Q and Tao, J and Ding, R and Wang, J and Cheng, N and Wang, M and Wang, F and Li, N and Xing, N and Chen, X and Fan, X and Wang, J and Wang, J},
title = {Humanized rodent models of neurodegenerative diseases and other brain disorders.},
journal = {Neuroscience and biobehavioral reviews},
volume = {172},
number = {},
pages = {106112},
doi = {10.1016/j.neubiorev.2025.106112},
pmid = {40120962},
issn = {1873-7528},
mesh = {Animals ; *Disease Models, Animal ; Humans ; *Neurodegenerative Diseases/genetics/pathology/physiopathology ; *Brain Diseases ; Rodentia ; },
abstract = {Central Nervous System (CNS) diseases significantly affect human health. However, replicating the onset, progression, and pathology of these diseases in rodents is challenging. To address this issue, researchers have developed humanized animal models. These models introduce human genes or cells into rodents. As a result, rodents become more suitable for studying human CNS diseases and their therapies in vivo. This review explores the preparation protocols, pathological and behavioral characteristics, benefits, significance, and limitations of humanized rodent models in researching various CNS diseases, particularly Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic lateral sclerosis, glial cells-related CNS diseases, N-methyl-D-aspartic acid receptor encephalitis, and others. Humanized rodent models have expanded the opportunities for in vivo exploration of human neurodegenerative diseases, other brain disorders, and their treatments. We can enhance translational research on CNS disorders by developing, investigating, and utilizing these models.},
}

Animals
*Disease Models, Animal
Humans
*Neurodegenerative Diseases/genetics/pathology/physiopathology
*Brain Diseases
Rodentia

@article {pmid40119776,
year = {2025},
author = {Pesti, B and Langa, X and Kumpesa, N and Valdeolivas, A and Sultan, M and Rottenberg, S and Hahn, K},
title = {Mini Review: Spatial Transcriptomics to Decode the Central Nervous System.},
journal = {Toxicologic pathology},
volume = {},
number = {},
pages = {1926233251325204},
doi = {10.1177/01926233251325204},
pmid = {40119776},
issn = {1533-1601},
abstract = {Spatial transcriptomics (ST) is revolutionizing our understanding of the central nervous system (CNS) by providing spatially resolved gene expression data. This mini review explores the impact of ST on CNS research, particularly in neurodegenerative diseases like Alzheimer's, Parkinson's, multiple sclerosis, and amyotrophic lateral sclerosis. We describe two foundational ST methods: sequencing-based and imaging-based. Key studies are reviewed highlighting the power of ST data sets to map transcriptomes to disease-specific histomorphology, elucidate molecular mechanisms of regional and cellular vulnerability, integrate single-cell data with tissue mapping, and reveal receptor-ligand interactions. Despite current challenges like data interpretation and resolution limits, ST holds promise for identifying novel drug targets, evaluating their therapeutic potential, and bridging gaps between animal models and human studies to advance development of CNS-targeting compounds.},
}

@article {pmid40118328,
year = {2025},
author = {Mansour, HM and El-Khatib, AS},
title = {Oligonucleotide-based therapeutics for neurodegenerative disorders: Focus on antisense oligonucleotides.},
journal = {European journal of pharmacology},
volume = {998},
number = {},
pages = {177529},
doi = {10.1016/j.ejphar.2025.177529},
pmid = {40118328},
issn = {1879-0712},
abstract = {Antisense oligonucleotides (ASOs) specifically bind to target RNA sequences and regulate protein expression through various mechanisms. ASOs are a promising therapeutic approach for treating neurodegenerative diseases. The ASO field is a growing area of drug development that focuses on targeting the root cause of diseases at the RNA level, providing a promising alternative to therapies that target downstream processes. Addressing challenges related to off-target effects and inadequate biological activity is essential to successfully develop ASO-based therapies. Researchers have investigated various chemical modifications and delivery strategies to overcome these challenges. This review discusses oligonucleotide-based therapies, particularly ASOs. We discuss the chemical modifications and mechanisms of action of ASOs. Additionally, we recap the results of preclinical and clinical studies testing different ASOs in various neurodegenerative disorders, including spinal muscular atrophy, Huntington's disease, amyotrophic lateral sclerosis, Alzheimer's disease, and Parkinson's disease. In conclusion, ASO drugs show promise as a therapeutic option for treating neurodegenerative diseases.},
}

@article {pmid40109277,
year = {2025},
author = {Ding, XY and Habimana, JD and Li, ZY},
title = {The role of DPP6 dysregulation in neuropathology: from synaptic regulation to disease mechanisms.},
journal = {Frontiers in cellular neuroscience},
volume = {19},
number = {},
pages = {1547495},
pmid = {40109277},
issn = {1662-5102},
abstract = {As a transmembrane protein, DPP6 modulates the function and properties of ion channels, playing a crucial role in various tissues, particularly in the brain. DPP6 interacts with potassium channel Kv4.2 (KCND2), enhancing its membrane expression and channel kinetics. Potassium ion channels are critical in progressing action potential formation and synaptic plasticity. Therefore, dysfunction of DPP6 can lead to significant health consequences. Abnormal DPP6 expression has been identified in several diseases, such as amyotrophic lateral sclerosis (ALS), autism spectrum disorder (ASD), spinal bulbar muscular atrophy (SBMA), and idiopathic ventricular fibrillation. Recent research has indicated a connection between DPP6 and Alzheimer's disease as well. The most common symptoms resulting from DPP6 dysregulation are mental deficiency and muscle wastage. Notably, these symptoms do not always occur at the same time. Besides genetic factors, environmental factors also undoubtedly play a role in diseases related to DPP6 dysregulation. However, it remains unclear how the expression of DPP6 gets regulated. This review aims to summarize the associations between DPP6 and neurological diseases, offering insights as well as proposing hypotheses to elucidate the underlying mechanisms of DPP6 dysregulation.},
}

@article {pmid40097762,
year = {2025},
author = {Nabakhteh, S and Lotfi, A and Afsartaha, A and Khodadadi, ES and Abdolghaderi, S and Mohammadpour, M and Shokri, Y and Kiani, P and Ehtiati, S and Khakshournia, S and Khatami, SH},
title = {Nutritional Interventions in Amyotrophic Lateral Sclerosis: From Ketogenic Diet and Neuroprotective Nutrients to the Microbiota-Gut-Brain Axis Regulation.},
journal = {Molecular neurobiology},
volume = {},
number = {},
pages = {},
pmid = {40097762},
issn = {1559-1182},
abstract = {Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disease with significant challenges in diagnosis and treatment. Recent research has highlighted the complex nature of ALS, encompassing behavioral impairments in addition to its neurological manifestations. While several medications have been approved to slow disease progression, ongoing research is focused on identifying new therapeutic targets. The current review focuses on emerging therapeutic strategies and personalized approaches aimed at improving patient outcomes. Recent advancements highlight the importance of targeting additional pathways such as mitochondrial dysfunction and neuroinflammation to develop more effective treatments. Personalized medicine, including genetic testing and biomarkers, is proving valuable in stratifying patients and tailoring treatment options. Complementary therapies, such as nutritional interventions like the ketogenic diet and microbiome modulation, also show promise. This review emphasizes the need for a multidisciplinary approach that integrates early diagnosis, targeted treatments, and supportive care to address the multisystemic nature of ALS and improve the quality of life for patients.},
}

@article {pmid40097438,
year = {2025},
author = {Ayyadurai, VAS and Deonikar, P and Kamm, RD},
title = {A molecular systems architecture of neuromuscular junction in amyotrophic lateral sclerosis.},
journal = {NPJ systems biology and applications},
volume = {11},
number = {1},
pages = {27},
pmid = {40097438},
issn = {2056-7189},
mesh = {*Amyotrophic Lateral Sclerosis/genetics/pathology ; *Neuromuscular Junction/metabolism/pathology ; Humans ; *Motor Neurons/pathology/metabolism ; Animals ; Systems Biology/methods ; },
abstract = {A molecular systems architecture is presented for the neuromuscular junction (NMJ) in order to provide a framework for organizing complexity of biomolecular interactions in amyotrophic lateral sclerosis (ALS) using a systematic literature review process. ALS is a fatal motor neuron disease characterized by progressive degeneration of the upper and lower motor neurons that supply voluntary muscles. The neuromuscular junction contains cells such as upper and lower motor neurons, skeletal muscle cells, astrocytes, microglia, Schwann cells, and endothelial cells, which are implicated in pathogenesis of ALS. This molecular systems architecture provides a multi-layered understanding of the intra- and inter-cellular interactions in the ALS neuromuscular junction microenvironment, and may be utilized for target identification, discovery of single and combination therapeutics, and clinical strategies to treat ALS.},
}

*Amyotrophic Lateral Sclerosis/genetics/pathology
*Neuromuscular Junction/metabolism/pathology
Humans
*Motor Neurons/pathology/metabolism
Animals
Systems Biology/methods

@article {pmid40095345,
year = {2025},
author = {Dehghani, S and Ocakcı, O and Hatipoglu, PT and Özalp, VC and Tevlek, A},
title = {Exosomes as Biomarkers and Therapeutic Agents in Neurodegenerative Diseases: Current Insights and Future Directions.},
journal = {Molecular neurobiology},
volume = {},
number = {},
pages = {},
pmid = {40095345},
issn = {1559-1182},
abstract = {Neurodegenerative diseases (NDs) like Alzheimer's, Parkinson's, and ALS rank among the most challenging global health issues, marked by substantial obstacles in early diagnosis and effective treatment. Current diagnostic techniques frequently demonstrate inadequate sensitivity and specificity, whilst conventional treatment strategies encounter challenges related to restricted bioavailability and insufficient blood-brain barrier (BBB) permeability. Recently, exosomes-nanoscale vesicles packed with proteins, RNAs, and lipids-have emerged as promising agents with the potential to reshape diagnostic and therapeutic approaches to these diseases. Unlike conventional drug carriers, they naturally traverse the BBB and can deliver bioactive molecules to affected neural cells. Their molecular cargo can influence cell signaling, reduce neuroinflammation, and potentially slow neurodegenerative progression. Moreover, exosomes serve as non-invasive biomarkers, enabling early and precise diagnosis while allowing real-time disease monitoring. Additionally, engineered exosomes, loaded with therapeutic molecules, enhance this capability by targeting diseased neurons and overcoming conventional treatment barriers. By offering enhanced specificity, reduced immunogenicity, and an ability to bypass physiological limitations, exosome-based strategies present a transformative advantage over existing diagnostic and therapeutic approaches. This review examines the multifaceted role of exosomes in NDDs, emphasizing their diagnostic capabilities, intrinsic therapeutic functions, and transformative potential as advanced treatment vehicles.},
}

@article {pmid40091916,
year = {2025},
author = {Ansari, U and Wen, J and Karabala, M and Syed, B and Abed, I and Razick, DI and Lui, F},
title = {Analysis of Respiratory Muscle Strength Training in Amyotrophic Lateral Sclerosis (ALS) Patients: A Systematic Review.},
journal = {Cureus},
volume = {17},
number = {2},
pages = {e78903},
pmid = {40091916},
issn = {2168-8184},
abstract = {Respiratory muscle weakness is a significant contributor to morbidity and mortality in amyotrophic lateral sclerosis (ALS) patients. Respiratory muscle strength training (RMST) has emerged as a potential therapeutic approach to mitigate respiratory muscle weakness in ALS. Still, its efficacy and safety remain unclear due to conflicting evidence and methodological heterogeneity in existing studies. A systematic review was conducted across three databases (PubMed (United States National Library of Medicine, Bethesda, MD, USA), Embase (Elsevier, Amsterdam, Netherlands), and Cochrane Library (Cochrane, Alberta, Canada)) following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to assess the effectiveness of RMST in ALS patients. Eligible studies included comparative studies for RMST, focusing on outcomes such as maximum inspiratory pressure (MIP), maximum expiratory pressure (MEP), forced vital capacity (FVC), and ALS Functional Rating Scale (ALSFRS-R). Quality assessment was performed using the Cochrane Risk of Bias tool. This study included six studies, including 183 patients with a mean age of 58.0 years (49.6 to 63.2) and a mean follow-up time of 21.2 weeks (eight to 52). The average mean difference for ALSFRS-R (three studies), MIP (three studies), MEP (three studies), and FVC (two studies) were 2.062 (0.04 to 5.3), 2.285 (-8.145 to 10.8), 19.435 (10.86 to 21.7), and 7.23 (3.6 to 10.86), respectively. Complications related to RMST were poorly reported across studies. Secondary outcomes, such as depression scores, blood oxygen levels, and heart rate variability, showed promising trends but lacked consistency. Despite positive findings on respiratory muscle strength, RMST's efficacy in ALS management remains inconclusive. Challenges include methodological heterogeneity, limited sample sizes, and inadequate reporting of complications. Future research should focus on standardized protocols, larger sample sizes, longer follow-ups, and comprehensive assessment of adverse effects to clarify the role of RMST in ALS treatment.},
}

@article {pmid40090808,
year = {2025},
author = {Rosina, M and Scaricamazza, S and Fenili, G and Nesci, V and Valle, C and Ferri, A and Paronetto, MP},
title = {Hidden players in the metabolic vulnerabilities of amyotrophic lateral sclerosis.},
journal = {Trends in endocrinology and metabolism: TEM},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.tem.2025.02.004},
pmid = {40090808},
issn = {1879-3061},
abstract = {Amyotrophic lateral sclerosis (ALS) is a complex and rapidly progressive motor neuron disorder with a fatal outcome. Despite the remarkable progress in understanding ALS pathophysiology, which has significantly contributed to clinical trial design, ALS remains a rapidly disabling and life-shortening condition. The non-motor neuron features of ALS, including nutritional status, energy expenditure, and metabolic imbalance, are increasingly gaining attention. Indeed, the bioenergetic failure and mitochondrial dysfunction of patients with ALS impact not only the high energy-demanding motor neurons but also organs and brain areas long considered irrelevant to the disease. As such, here we discuss how considering energy balance in ALS is reshaping research on this disease, opening the path to novel targetable opportunities for its treatment.},
}

@article {pmid40089090,
year = {2025},
author = {Men, J and Wang, X and Zhou, Y and Huang, Y and Zheng, Y and Wang, Y and Yang, S and Chen, N and Yan, N and Duan, X},
title = {Neurodegenerative diseases: Epigenetic regulatory mechanisms and therapeutic potential.},
journal = {Cellular signalling},
volume = {131},
number = {},
pages = {111715},
doi = {10.1016/j.cellsig.2025.111715},
pmid = {40089090},
issn = {1873-3913},
mesh = {Humans ; *Epigenesis, Genetic ; *Neurodegenerative Diseases/genetics/therapy/pathology ; DNA Methylation ; Animals ; Histones/metabolism ; RNA, Untranslated/genetics/metabolism ; Chromatin Assembly and Disassembly ; },
abstract = {Neurodegenerative diseases (NDDs) are a class of diseases in which the progressive loss of subtype-specific neurons leads to dysfunction. NDDs include Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), among others. Previous studies have demonstrated that the pathogenesis of NDDs involves various mechanisms, including genetic factors, oxidative stress, apoptosis, and the immune response. Recent studies have shown that epigenetic regulation mediates the interactions between DNA methylation, chromatin remodeling, histone modification, and non-coding RNAs, thus affecting gene transcription. A growing body of research links epigenetic modifications to crucial pathways involved in the occurrence and development of NDDs. Epigenetics has also been found to regulate and maintain nervous system function, and its imbalance is closely related to the occurrence and development of NDDs. The present review summarizes focuses on the role of epigenetic modifications in the pathogenesis of NDDs and provides an overview of the key genes regulated by DNA methylation, histone modification, and non-coding RNAs in NDDs. Further, the current research status of epigenetics in NDDs is summarized and the potential application of epigenetics in the clinical diagnosis and treatment of NDDs is discussed.},
}

Humans
*Epigenesis, Genetic
*Neurodegenerative Diseases/genetics/therapy/pathology
DNA Methylation
Animals
Histones/metabolism
RNA, Untranslated/genetics/metabolism
Chromatin Assembly and Disassembly

@article {pmid40086112,
year = {2025},
author = {Liampas, I and Veltsista, D and Germeni, A and Batzikosta, P and Michou, E and Kefalopoulou, Z and Chroni, E},
title = {F waves in amyotrophic lateral sclerosis: A systematic review and meta-analysis.},
journal = {Neurophysiologie clinique = Clinical neurophysiology},
volume = {55},
number = {4},
pages = {103061},
doi = {10.1016/j.neucli.2025.103061},
pmid = {40086112},
issn = {1769-7131},
abstract = {OBJECTIVE: This systematic review and meta-analysis aimed to determine the pattern of F-wave abnormalities and their potential utility in the early diagnosis of amyotrophic lateral sclerosis (ALS).

METHODS: Medline and Embase were thoroughly searched. We primarily emphasized F-wave recordings from the abductor digiti minimi, following stimulation of the ulnar nerve at the wrist. Data from case-control studies involving individuals with ALS versus healthy controls (HC) or other well-defined patient groups were reviewed and -if appropriate- quantitatively synthesized.

RESULTS: Twenty-nine studies were included in this systematic review and 17 of them in the analytic part. The pattern of F-abnormalities in ALS compared to HC was as follows: decreased persistence (MD=20.25 %,15.67-24.84 %), mildly prolonged minimum latency (MD=1.59msec,1.11-2.06msec), increased maximum amplitude (MD=196μV,106-287μV) and elevated Index total Freps (MD=33.9 %,26.0-41.8 %). Affected limbs (with substantial weakness in clinical examination and/or muscle wasting and/or abnormal nerve conduction studies) exhibited more marked abnormalities in persistence, minimum latency, and Index total Freps, whereas abnormalities in these parameters were very mild in clinically unaffected limbs. More prominent increases in maximum amplitude accompanied pyramidal dysfunction. Of note, isolated upper motor neuron (UMN) disorders exhibited a comparable increase in Index total Freps without a decrease in persistence.

CONCLUSIONS: The pattern of F wave abnormalities may raise suspicion of involvement of the under-study lower motor neuron (LMN) pool in ALS. These findings may identify LMN dysfunction even at a preclinical stage and prompt extensive electromyographic investigations. UMN involvement may to some extent differentiate the profile of F wave abnormalities in ALS.},
}

@article {pmid40080233,
year = {2025},
author = {Aydın, Ş and Özdemir, S and Adıgüzel, A},
title = {The Potential of cfDNA as Biomarker: Opportunities and Challenges for Neurodegenerative Diseases.},
journal = {Journal of molecular neuroscience : MN},
volume = {75},
number = {1},
pages = {34},
pmid = {40080233},
issn = {1559-1166},
mesh = {Humans ; *Biomarkers/blood ; *Cell-Free Nucleic Acids/blood ; *Neurodegenerative Diseases/blood/diagnosis/genetics ; Animals ; },
abstract = {Neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS), are characterized by the progressive and gradual degeneration of neurons. The prevalence and rates of these disorders rise significantly with age. As life spans continue to increase in many countries, the number of cases is expected to grow in the foreseeable future. Early and precise diagnosis, along with appropriate surveillance, continues to pose a challenge. The high heterogeneity of neurodegenerative diseases calls for more accurate and definitive biomarkers to improve clinical therapy. Cell-free DNA (cfDNA), including fragmented DNA released into bodily fluids via apoptosis, necrosis, or active secretion, has emerged as a promising non-invasive diagnostic tool for various disorders including neurodegenerative diseases. cfDNA can serve as an indicator of ongoing cellular damage and mortality, including neuronal loss, and may provide valuable insights into disease processes, progression, and therapeutic responses. This review will first cover the key aspects of cfDNA and then examine recent advances in its potential use as a biomarker for neurodegenerative disorders.},
}

Humans
*Biomarkers/blood
*Cell-Free Nucleic Acids/blood
*Neurodegenerative Diseases/blood/diagnosis/genetics
Animals

@article {pmid40077653,
year = {2025},
author = {de Carvalho Vilar, MD and Coutinho, KMD and de Lima Vale, SH and Dourado Junior, MET and de Medeiros, GCBS and Piuvezam, G and Brandao-Neto, J and Leite-Lais, L},
title = {Evidence-Based Nutritional Recommendations for Maintaining or Restoring Nutritional Status in Patients with Amyotrophic Lateral Sclerosis: A Systematic Review.},
journal = {Nutrients},
volume = {17},
number = {5},
pages = {},
pmid = {40077653},
issn = {2072-6643},
support = {grant number 302298/2017-7 (Jose Brandao-Neto)//National Council for Scientific and Technological Development/ ; TED 132/2018//Ministry of Health (Brazil) - Laboratory of Technological Innovation in Health from the Federal University of Rio Grande do Norte - LAIS/UFRN/ ; },
mesh = {*Amyotrophic Lateral Sclerosis/diet therapy/therapy/complications ; Humans ; *Nutritional Status ; *Nutrition Assessment ; Evidence-Based Medicine ; Quality of Life ; Nutritional Support/methods ; Dietary Supplements ; Deglutition Disorders/diet therapy/therapy ; Gastrostomy ; Nutrition Therapy/methods ; },
abstract = {Background/Objectives: This study is a systematic review of guidelines that aims to synthesize evidence-based recommendations to support appropriate nutritional management for patients with amyotrophic lateral sclerosis (ALS). Methods: PubMed/MEDLINE, Embase, Scopus, SciELO, Web of Science, LILACS, ScienceDirect, and Google Scholar were searched for records published up to July 2024. Clinical practice guidelines addressing any aspect of nutritional intervention in ALS were included. No language or country of publication restrictions were applied. Data extraction was performed by two independent reviewers. The methodological quality of the reports was assessed using the AGREE II instrument. Discrepancies were resolved by consensus. Results: The findings and main recommendations were summarized narratively. A total of 837 records were identified, and 11 were included in this review. The overall AGREE II scores for the included studies ranged from 3 to 7. The summary of nutritional recommendations was organized into topics: (1) dysphagia, (2) nutritional assessment, (3) energy, (4) protein, (5) supplementation, and (6) percutaneous endoscopic gastrostomy (PEG). This review summarizes relevant and updated nutritional recommendations to maintain or restore the nutritional status of patients with ALS, contributing to their quality of life and survival time. Conclusions: These nutritional recommendations will help health professionals and caregivers to implement and standardize nutritional care according to evidence-based practice in ALS. PROSPERO registration number CRD42021233088.},
}

*Amyotrophic Lateral Sclerosis/diet therapy/therapy/complications
Humans
*Nutritional Status
*Nutrition Assessment
Evidence-Based Medicine
Quality of Life
Nutritional Support/methods
Dietary Supplements
Deglutition Disorders/diet therapy/therapy
Gastrostomy
Nutrition Therapy/methods

@article {pmid40074390,
year = {2025},
author = {Cappa, SF},
title = {Hemispheric asymmetry in neurodegenerative diseases.},
journal = {Handbook of clinical neurology},
volume = {208},
number = {},
pages = {101-112},
doi = {10.1016/B978-0-443-15646-5.00009-9},
pmid = {40074390},
issn = {0072-9752},
mesh = {Humans ; *Neurodegenerative Diseases/pathology/physiopathology ; *Functional Laterality/physiology ; Brain/pathology/physiopathology ; },
abstract = {Hemispheric asymmetry in pathologic involvement is frequently observed in neurodegenerative disorders (NDD) and is responsible for differences in cognitive and motor clinical manifestations in individual patients. While asymmetry is modest in typical Alzheimer disease (AD), atypical AD presentations with prominent language impairment [logopenic/phonologic variant of primary progressive aphasia (L/Phv-PPA)] are associated with prevalent involvement of the language-dominant hemisphere. Similarly, in the frontotemporal dementia-amyotrophic lateral sclerosis (FTD-ALS) spectrum, the semantic (Sv) and nonfluent/agrammatic (Nf/Av) variants of PPA are due to asymmetric pathology involving the language-dominant hemisphere. A reversed (typically right-sided) pattern of asymmetry is often found in conditions associated with prominent disorders of behavior and social cognition (i.e., behavioral variant of frontotemporal degeneration-Bv FTD). Asymmetry is generally modest and less consistent in NDD with prevalent motor manifestations, such as Parkinson disease (PD). Overall, the pattern of hemispheric involvement reflects the network-specific selectivity of NDD and is compatible with the spreading of pathology along connection pathways.},
}

Humans
*Neurodegenerative Diseases/pathology/physiopathology
*Functional Laterality/physiology
Brain/pathology/physiopathology

@article {pmid40072076,
year = {2025},
author = {Calvo, B and Schembri-Wismayer, P and Durán-Alonso, MB},
title = {Age-Related Neurodegenerative Diseases: A Stem Cell's Perspective.},
journal = {Cells},
volume = {14},
number = {5},
pages = {},
pmid = {40072076},
issn = {2073-4409},
mesh = {Humans ; *Neurodegenerative Diseases/pathology ; *Aging/pathology ; Animals ; Stem Cells/metabolism ; Neurogenesis ; },
abstract = {Neurodegenerative diseases encompass a number of very heterogeneous disorders, primarily characterized by neuronal loss and a concomitant decline in neurological function. Examples of this type of clinical condition are Alzheimer's Disease, Parkinson's Disease, Huntington's Disease and Amyotrophic Lateral Sclerosis. Age has been identified as a major risk in the etiology of these disorders, which explains their increased incidence in developed countries. Unfortunately, despite continued and intensive efforts, no cure has yet been found for any of these diseases; reliable markers that allow for an early diagnosis of the disease and the identification of key molecular events leading to disease onset and progression are lacking. Altered adult neurogenesis appears to precede the appearance of severe symptoms. Given the scarcity of human samples and the considerable differences with model species, increasingly complex human stem-cell-based models are being developed. These are shedding light on the molecular alterations that contribute to disease development, facilitating the identification of new clinical targets and providing a screening platform for the testing of candidate drugs. Moreover, the secretome and other promising features of these cell types are being explored, to use them as replacement cells of high plasticity or as co-adjuvant therapy in combinatorial treatments.},
}

Humans
*Neurodegenerative Diseases/pathology
*Aging/pathology
Animals
Stem Cells/metabolism
Neurogenesis

@article {pmid40069959,
year = {2025},
author = {Chiò, A and Foucher, J and Gwathmey, KG and Ingre, C},
title = {Minimum clinically important difference for drug effectiveness in an area of patient-oriented therapeutic goals in amyotrophic lateral sclerosis.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-10},
doi = {10.1080/21678421.2025.2475893},
pmid = {40069959},
issn = {2167-9223},
abstract = {Objective: In this review, we will examine the more common endpoints incorporated in randomized controlled trials (RCTs) and their strength of evidence, focusing on the definition of what constitutes a clinically meaningful change. We will also reflect on the perspective of patients and their families regarding the design of RCTs in amyotrophic lateral sclerosis (ALS). Methods: Authors performed a scoping review of the literature around clinical meaningfulness in the ALS field and the minimum clinically important difference to deem a treatment effective. Results: The use of survival as an RCT endpoint, as well as the ALS functional rating scale-revised slope, has been criticized, and their relevance for patients remains debated. Biomarkers are promising alternatives as surrogate endpoints, but currently, only cerebrospinal fluid and plasma neurofilaments have emerged as reliable and sensitive biomarkers of disease progression. Incorporating patients' preferences and priorities for their care when treatments are selected is important to minimize the burden of care and limit the potential harms of overtreatment. Patients' interest in and acceptance of a new therapy is also determined by its impact on their quality of life. Discussion and conclusion: While scientifically sound trials must be conducted, this must be balanced with patient expectations of limiting trial burden, duration and placebo usage. An important approach in uniting these diverging needs is the inclusion of people with ALS and their organizations to advise in the design and execution of clinical trials, facilitating the design of RCTs more focused on patients' expectations while retaining a high scientific rigor.},
}

@article {pmid40065552,
year = {2025},
author = {Shibata, N and Kataoka, I and Okamura, Y and Murakami, K and Kato, Y and Yamamoto, T and Masui, K},
title = {Implications for soluble iron accumulation, oxidative stress, and glial glutamate release in motor neuron death associated with sporadic amyotrophic lateral sclerosis.},
journal = {Neuropathology : official journal of the Japanese Society of Neuropathology},
volume = {},
number = {},
pages = {},
doi = {10.1111/neup.13033},
pmid = {40065552},
issn = {1440-1789},
abstract = {Oxidative stress in sporadic amyotrophic lateral sclerosis (ALS) has been evidenced by accumulation of oxidatively modified products of nucleic acids, lipids, sugars, and proteins in the motor neuron system of brains and spinal cords obtained at autopsy from the patients. We recently demonstrated soluble iron accumulation in activated microglia of sporadic ALS spinal cords. This finding could indicate that iron-mediated Fenton reaction is most likely to be responsible for oxidative stress associated with this disease. The excitatory amino acid neurotoxicity hypothesis for sporadic ALS has been proposed based on increased glutamate and aspartate concentrations in cerebrospinal fluid from the patients. Initially, the increase in extracellular excitatory amino acid levels was considered to reflect excessive release from the axon terminal of upper motor neurons. However, it is a question of whether the damaged upper motor neurons continue releasing glutamate even in advanced stage of this disease. To address this issue, we hypothesized that glial cells might be a glutamate release source. Our immunohistochemical analysis on autopsied human spinal cords revealed that ferritin, hepcidin, ferroportin, aconitase 1, tumor necrosis factor-α (TNF-α), TNF-α-converting enzyme (TACE), and glutaminase-C (GAC) were expressed mainly in microglia and that cystine/glutamate antiporter (xCT) was expressed mainly in astrocytes. We next performed cell culture experiments. Cultured microglia treated with soluble iron over-released glutamate and TNF-α via aconitase 1 and TACE, respectively. Cultured microglia treated with TNF-α over-released glutamate via GAC. Cultured microglia treated with hepcidin, of which expression is known to be upregulated by TNF-α, showed downregulated expression of ferroportin. Cultured astrocytes treated with hydrogen peroxide over-released glutamate via xCT. These observations provide in vivo and in vitro evidence that microglia and astrocytes are glutamate suppliers in response to soluble iron overload and oxidative stress, respectively, in sporadic ALS.},
}

@article {pmid40060160,
year = {2025},
author = {Mangalindan, KE and Wyatt, TR and Brown, KR and Shapiro, M and Maggio, LA},
title = {Investigating the Road to Equity: A Scoping Review of Solutions to Mitigate Implicit Bias in Assessment within Medical Education.},
journal = {Perspectives on medical education},
volume = {14},
number = {1},
pages = {92-106},
pmid = {40060160},
issn = {2212-277X},
mesh = {Humans ; *Education, Medical/methods ; Bias ; Educational Measurement/methods ; },
abstract = {INTRODUCTION: In medical education, assessments have high-stakes implications. Yet, assessments are rife with unconscious bias, which contributes to inequitable social structures. Implicit bias in assessment must be addressed because medical educators use assessments to guide learning and promote development of physicians' careers. In this scoping review, the authors map the literature on implicit bias in assessment, as it applies to: 1) the types of implicit bias addressed, 2) the targets and types of interventions studied or proposed, and 3) how publications describe intervention efficacy.

METHODS: The authors conducted a scoping review of the literature on interventions to mitigate implicit bias that was published between January 2010 and August 2023. Author pairs independently screened articles for inclusion and extracted data. Discrepancies were resolved with discussion and consensus. Qualitative and quantitative analysis was informed by Anderson et al's three assessment orientations: fairness, assessment for inclusion (AfI), and justice.

RESULTS: 7,831 articles were identified; 54 articles were included. The majority (n = 37; 69%) of articles focus on implicit bias toward those underrepresented in medicine. Interventions to mitigate implicit bias were targeted toward admissions and applications, faculty training, recruitment, summative assessments, and evaluation templates. Interventions had fairness (n = 43; 96%) and AfI (n = 22; 49%) orientations; no articles used a justice-orientation. For the sub-set of research studies (n = 40), almost all (n = 34; 85%) examined a single program/institution.

DISCUSSION: This scoping review showed that more work is necessary to address different types of implicit biases, move scholarship beyond single-institution studies, refine existing interventions, and evaluate how efficacy is defined.},
}

Humans
*Education, Medical/methods
Bias
Educational Measurement/methods

@article {pmid40057669,
year = {2025},
author = {Hatcher, H and Stankeviciute, S and Learn, C and Qu, AX},
title = {Regulatory, Translational, and Operational Considerations for the Incorporation of Biomarkers in Drug Development.},
journal = {Therapeutic innovation & regulatory science},
volume = {59},
number = {3},
pages = {519-526},
pmid = {40057669},
issn = {2168-4804},
abstract = {BACKGROUND: Biomarkers are an integral component in the drug development paradigm. According to the US Food and Drug Administration (FDA), a biomarker is "a defined characteristic that is measured as an indicator of normal biological processes, pathogenic processes, or biological responses to an exposure or intervention, including therapeutic intervention" (FDA-NIH Biomarker Working Group. BEST (Biomarkers, EndpointS, and other Tools) Resource [Internet]. Silver Spring (MD): Food and Drug Administration (US); 2016-. Glossary. 2016 [Updated 2021 Nov 29, cited 2024 Apr 14]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK338448/ Co-published by National Institutes of Health (US), Bethesda (MD)). The European Medicines Agency (EMA) defines a biomarker as "an objective and quantifiable measure of a physiological process, pathological process or response to a treatment (excluding measurements of how an individual feels or functions" European Medicines Agency (EMA). Biomaker. 2020a. Available from: https://www.ema.europa.eu/en/glossary-terms/biomarker#:~:text=Biomarker-,Biomarker,an%20individual%20feels%20or%20functions . Several clinical biomarkers are well-documented and have been used routinely for decades in health care settings and have long been accepted as valid endpoints for drug approval (for example, blood pressure measurement as a biomarker for cardiovascular health) (European Medicines Agency (EMA). Assessment report, TAGRISSO. 2016. Available from: https://www.ema.europa.eu/en/documents/assessment-report/tagrisso-epar-public-assessment-report_en.pdf . Accessed 15 Apr 2024). Recently, novel biomarkers have been identified and validated to accelerate developing innovative therapies indicated for serious human diseases, for example targeted/immune therapies of cancer (Chen in Med Drug Discov 21:100174, 2024). As indicators of the efficacy of new pharmacological treatments or therapeutic interventions, biomarkers can improve clinical trial efficacy and reduce uncertainty in regulatory decision making (Bakker et al. in Clin Pharmacol Ther 112:69-80, 2022; Califf in Exp Biol Med 243:213-221, 2018; Parker et al. in Cancer Med 10:1955-1963, 2021).

METHODOLOGY: This article describes case studies of recent drug approvals that successfully leveraged validated and non-validated biomarkers (i.e., tofersen for the neurodegenerative disease amyotrophic lateral sclerosis (ALS) in adults; and osimertinib for treatment of patients with metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive non-small cell lung cancer (NSCLC)).

CONCLUSIONS: Best practices for biomarker selection and strategies for health authority biomarker qualification programs are presented along with an overview of current limitations and challenges to optimizing biomarker applications along the drug development continuum from regulatory, translational, and operational perspectives.},
}

@article {pmid40056503,
year = {2025},
author = {Zhan, A and Zhong, K and Zhang, K},
title = {Novel subcellular regulatory mechanisms of protein homeostasis and its implications in amyotrophic lateral sclerosis.},
journal = {Biochemical and biophysical research communications},
volume = {756},
number = {},
pages = {151582},
doi = {10.1016/j.bbrc.2025.151582},
pmid = {40056503},
issn = {1090-2104},
mesh = {*Amyotrophic Lateral Sclerosis/metabolism/pathology ; Humans ; *Proteostasis ; Animals ; Mitochondria/metabolism ; Protein Aggregates ; Homeostasis ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron degenerative disorder. Protein aggregates induce various forms of neuronal dysfunction and represent pathological hallmarks in ALS patients. Reducing protein aggregates could be a promising therapeutic strategy for ALS. While most studies have focused on cytoplasmic protein homeostasis, neurons adaptively reduce aggregates across subcellular compartments during stress through previously uncharacterized mechanisms. Here, we summarize novel compartment-specific proteostatic mechanisms: (1) the ERAD/RESET pathways, (2) HSPs-mediated nuclear sequestration, (3) mitochondrial aggregate import (MAGIC), (4) neurite-localized UPS/autophagosome and NMP, and (5) exopher-mediated extracellular disposal. These mechanisms collectively ensure cellular stress adaptation and provide novel therapeutic targets for ALS treatment.},
}

*Amyotrophic Lateral Sclerosis/metabolism/pathology
Humans
*Proteostasis
Animals
Mitochondria/metabolism
Protein Aggregates
Homeostasis

@article {pmid40046336,
year = {2025},
author = {Öztürk, MM and Emgård, J and García-Revilla, J and Fernández-Calle, R and Yang, Y and Deierborg, T and Roos, TT},
title = {The role of microglia in the prion-like transmission of protein aggregates in neurodegeneration.},
journal = {Brain communications},
volume = {7},
number = {2},
pages = {fcaf087},
pmid = {40046336},
issn = {2632-1297},
abstract = {Numerous neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis share a neuropathological hallmark: aberrant protein aggregation in the CNS. Microglia, the brain's innate immune cells, also play a pivotal role in the pathogenesis of these disorders. Multiple studies indicate that these pathological aggregates can propagate throughout the brain in a prion-like manner. A protein/peptide that adopts a prion-like conformation can induce homologous proteins to misfold into a prion-like conformation through templated seeding, enabling cell-to-cell spread and accelerating protein aggregation throughout the brain. Two important questions in the prion-like paradigm are where the prion-like misfolding occurs and how the prion-like aggregates are spread throughout the CNS. Here, we review the role of microglia and associated inflammation in the prion-like spread of pathologically aggregated proteins/peptides in Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. A growing body of evidence suggests that microglia can internalize prion-like proteins and transport them to neighbouring neurons and other glial cells. Microglia may also influence the potential seeding of proteins in neurons and induce inflammatory pathways in their microenvironment. This review aims to broaden the understanding of the role of microglia in the prion-like spread of protein aggregation.},
}

@article {pmid40045432,
year = {2025},
author = {Blair, K and Martinez-Serra, R and Gosset, P and Martín-Guerrero, SM and Mórotz, GM and Atherton, J and Mitchell, JC and Markovinovic, A and Miller, CCJ},
title = {Structural and functional studies of the VAPB-PTPIP51 ER-mitochondria tethering proteins in neurodegenerative diseases.},
journal = {Acta neuropathologica communications},
volume = {13},
number = {1},
pages = {49},
pmid = {40045432},
issn = {2051-5960},
support = {MR/X021858/1//UK Research and Innovation/ ; },
mesh = {Humans ; *Neurodegenerative Diseases/metabolism/pathology ; *Endoplasmic Reticulum/metabolism ; *Vesicular Transport Proteins/metabolism ; Animals ; *Mitochondria/metabolism ; Mitochondrial Proteins/metabolism ; Protein Tyrosine Phosphatases/metabolism ; },
abstract = {Signaling between the endoplasmic reticulum (ER) and mitochondria regulates many of the seemingly disparate physiological functions that are damaged in neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). A number of studies have now demonstrated that ER-mitochondria signaling is perturbed in these diseases and there is evidence that this may be a driving mechanism in disease onset and progression. VAPB and PTPIP51 are ER-mitochondria tethering proteins; VAPB is an ER protein and PTPIP51 is an outer mitochondrial membrane protein and the two proteins interact to enable inter-organelle signaling. The VAPB-PTPIP51 interaction is disrupted in Alzheimer's disease, Parkinson's disease, FTD and ALS. Here we review the roles of VAPB and PTPIP51 in ER-mitochondria signaling and the mechanisms by which neurodegenerative disease insults may disrupt the VAPB-PTPIP51 interaction.},
}

Humans
*Neurodegenerative Diseases/metabolism/pathology
*Endoplasmic Reticulum/metabolism
*Vesicular Transport Proteins/metabolism
Animals
*Mitochondria/metabolism
Mitochondrial Proteins/metabolism
Protein Tyrosine Phosphatases/metabolism

@article {pmid40041912,
year = {2025},
author = {Dash, UC and Bhol, NK and Swain, SK and Samal, RR and Nayak, PK and Raina, V and Panda, SK and Kerry, RG and Duttaroy, AK and Jena, AB},
title = {Oxidative stress and inflammation in the pathogenesis of neurological disorders: Mechanisms and implications.},
journal = {Acta pharmaceutica Sinica. B},
volume = {15},
number = {1},
pages = {15-34},
pmid = {40041912},
issn = {2211-3835},
abstract = {Neuroprotection is a proactive approach to safeguarding the nervous system, including the brain, spinal cord, and peripheral nerves, by preventing or limiting damage to nerve cells and other components. It primarily defends the central nervous system against injury from acute and progressive neurodegenerative disorders. Oxidative stress, an imbalance between the body's natural defense mechanisms and the generation of reactive oxygen species, is crucial in developing neurological disorders. Due to its high metabolic rate and oxygen consumption, the brain is particularly vulnerable to oxidative stress. Excessive ROS damages the essential biomolecules, leading to cellular malfunction and neurodegeneration. Several neurological disorders, including Alzheimer's, Parkinson's, Amyotrophic lateral sclerosis, multiple sclerosis, and ischemic stroke, are associated with oxidative stress. Understanding the impact of oxidative stress in these conditions is crucial for developing new treatment methods. Researchers are exploring using antioxidants and other molecules to mitigate oxidative stress, aiming to prevent or slow down the progression of brain diseases. By understanding the intricate interplay between oxidative stress and neurological disorders, scientists hope to pave the way for innovative therapeutic and preventive approaches, ultimately improving individuals' living standards.},
}

@article {pmid40038221,
year = {2025},
author = {Mustafa, F and Mittal, S and Garg, D and Agarwal, A and Garg, A and Gupta, BK and Soneja, M and Srivastava, AK},
title = {HIV associated motor neuron disease (MND): A case series with systematic review of literature.},
journal = {Journal of neurovirology},
volume = {31},
number = {1},
pages = {1-15},
pmid = {40038221},
issn = {1538-2443},
mesh = {Humans ; *HIV Infections/drug therapy/complications/virology ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/virology/drug therapy/diagnostic imaging/pathology ; Female ; Adult ; *Motor Neuron Disease/virology/drug therapy ; Viral Load ; CD4 Lymphocyte Count ; Anti-HIV Agents/therapeutic use ; },
abstract = {Human immunodeficiency virus (HIV) associated motor neuron disease (MND) is very rare. HIV infection can cause an MND-like syndrome due to central nervous system (CNS) involvement de novo or during antiretroviral therapy (ART) due to CNS escape. We present two cases: one with a classic amyotrophic lateral sclerosis (ALS) phenotype, which was the manifestation of symptomatic CNS escape from ART, and the second with a primary lateral sclerosis (PLS) phenotype associated with underlying HIV infection. A systematic review of published literature of people living with HIV (PLHIV) who developed ALS/ MND was conducted using the PubMed, Embase, and Lilacs databases. A total of 91 cases were found, 89 of which were obtained from 37 articles, and two were included from our own case series. In patients with HIV-associated MND, 63 patients reviewed had a classic ALS phenotype followed by progressive muscular atrophy variant (12), progressive bulbar palsy (8), PLS (7) and bulbar onset ALS (1). Neuroimaging, electrophysiology, cerebrospinal fluid (CSF) analysis, CSF and serum HIV viral load, and CD4 count investigations were used for diagnosis. Following the initiation or modification of antiretroviral therapy (ART), approximately 70% exhibited an improvement or a stable disease course. HIV-associated MND is a rare condition that can occur in both ART-naive individuals and those on treatment. A proportion of cases (~ 70%) show improvement with ART. Accurate diagnosis requires the exclusion of opportunistic infections, which remains a critical yet challenging aspect of managing this condition.},
}

Humans
*HIV Infections/drug therapy/complications/virology
Male
Middle Aged
*Amyotrophic Lateral Sclerosis/virology/drug therapy/diagnostic imaging/pathology
Female
Adult
*Motor Neuron Disease/virology/drug therapy
Viral Load
CD4 Lymphocyte Count
Anti-HIV Agents/therapeutic use

@article {pmid40037468,
year = {2025},
author = {Peck, A and Dadi, A and Yavarow, Z and Alfano, LN and Anderson, D and Arkin, MR and Chou, TF and D'Ambrosio, ES and Diaz-Manera, J and Dudley, JP and Elder, AG and Ghoshal, N and Hart, CE and Hart, MM and Huryn, DM and Johnson, AE and Jones, KB and Kimonis, V and Kiskinis, E and Lee, EB and Lloyd, TE and Mapstone, M and Martin, A and Meyer, H and Mozaffar, T and Onyike, CU and Pfeffer, G and Pindon, A and Raman, M and Richard, I and Rubinsztein, DC and Schiava, M and Schütz, AK and Shen, PS and Southworth, DR and Staffaroni, AM and Taralio-Gravovac, M and Weihl, CC and Yao, Q and Ye, Y and Peck, N},
title = {2024 VCP International Conference: Exploring multi-disciplinary approaches from basic science of valosin containing protein, an AAA+ ATPase protein, to the therapeutic advancement for VCP-associated multisystem proteinopathy.},
journal = {Neurobiology of disease},
volume = {207},
number = {},
pages = {106861},
pmid = {40037468},
issn = {1095-953X},
support = {R01 CA293084/CA/NCI NIH HHS/United States ; Z99 DK999999/ImNIH/Intramural NIH HHS/United States ; },
mesh = {*Valosin Containing Protein/genetics/metabolism ; Humans ; Animals ; Myositis, Inclusion Body/genetics/therapy/metabolism ; Frontotemporal Dementia/genetics/therapy ; },
abstract = {Valosin-containing protein (VCP/p97) is a ubiquitously expressed AAA+ ATPase associated with numerous protein-protein interactions and critical cellular functions including protein degradation and clearance, mitochondrial homeostasis, DNA repair and replication, cell cycle regulation, endoplasmic reticulum-associated degradation, and lysosomal functions including autophagy and apoptosis. Autosomal-dominant missense mutations in the VCP gene may result in VCP-associated multisystem proteinopathy (VCP-MSP), a rare degenerative disorder linked to heterogeneous phenotypes including inclusion body myopathy (IBM) with Paget's disease of bone (PDB) and frontotemporal dementia (FTD) or IBMPFD, amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), parkinsonism, Charcot-Marie Tooth disease (CMT), and spastic paraplegia. The complexity of VCP-MSP makes collaboration among stakeholders essential and necessitates a multi-disciplinary approach. The 2024 VCP International Conference was hosted at Caltech between February 22 and 25. Co-organized by Cure VCP Disease and Dr. Tsui-Fen Chou, the meeting aimed to center the patient as a research partner, harmonize diverse stakeholder engagement, and bridge the gap between basic and clinical neuroscience as it relates to VCP-MSP. Over 100 multi-disciplinary experts attended, ranging from basic scientists to clinicians to patient advocates. Attendees discussed genetics and clinical presentation, cellular and molecular mechanisms underlying disease, therapeutic approaches, and strategies for future VCP research. The conference included three roundtable discussions, 29 scientific presentations, 32 scientific posters, nine patient and caregiver posters, and a closing discussion forum. The following conference proceedings summarize these sessions, highlighting both the identified gaps in knowledge and the significant strides made towards understanding and treating VCP diseases.},
}

*Valosin Containing Protein/genetics/metabolism
Humans
Animals
Myositis, Inclusion Body/genetics/therapy/metabolism
Frontotemporal Dementia/genetics/therapy

@article {pmid40033997,
year = {2025},
author = {Poulsen, NS and Kraglund, LR and Vissing, J},
title = {Physical training of wheelchair users with neuromuscular disorders: A systematic review.},
journal = {Journal of neuromuscular diseases},
volume = {},
number = {},
pages = {22143602241313114},
doi = {10.1177/22143602241313114},
pmid = {40033997},
issn = {2214-3602},
abstract = {OBJECTIVE: Wheelchair users with neuromuscular disorders have symptoms related to the disease and complications to the sedentary lifestyle, such as constipation and lower back pain. Physical training might be beneficial. This systematic review investigates the potential benefits and harms of physical training for wheelchair users with neuromuscular disorders.

METHODS: We systematically searched PubMed including studies published until July 2024. Inclusion criteria: 1) participants with a neuromuscular disorder, 2) at least 60% of participants in a study were wheelchair users, 3) physical training and its effects were investigated, 4) studies were prospective, and 5) English language was used. Non-peer-reviewed articles were excluded. Search results were screened by title, abstract, and full text. Two independent authors assessed the quality with the Downs and Black Quality Index.

RESULTS: We included 14 studies of 140 patients from 5 types of neuromuscular disorders (Duchenne muscular atrophy, spinal muscular atrophy, limb-girdle muscular atrophy, facioscapulohumeral muscular dystrophy, and amyotrophic lateral sclerosis). The mean quality was low (16/32) due to flaws in study design, selection bias, and power. Even though many were of low quality and lacked descriptions of adverse events, they all showed positive effects. Most studies investigated physical training of mastication or respiration with improvements in both. Other findings were improvements in endurance, extremity strength, and range of motion.

CONCLUSIONS: Physical training of wheelchair users with neuromuscular disorders is not well investigated. Physical training seems safe and beneficial, but training of respiratory and masticatory muscles is the only well-documented exercise modality that can be advised in patients with Duchenne Muscular Dystrophy or Duchenne Muscular Dystrophy/Spinal Muscular Atrophy, respectively. Larger, high-quality trials, including other neuromuscular disorders, are needed to assess the effects and adverse events of physical training.},
}

@article {pmid40032118,
year = {2025},
author = {Dang, M and Wu, L and Zhang, X},
title = {Structural insights and milestones in TDP-43 research: A comprehensive review of its pathological and therapeutic advances.},
journal = {International journal of biological macromolecules},
volume = {306},
number = {Pt 3},
pages = {141677},
doi = {10.1016/j.ijbiomac.2025.141677},
pmid = {40032118},
issn = {1879-0003},
abstract = {Transactive response (TAR) DNA-binding protein 43 (TDP-43) is a critical RNA/DNA-binding protein involved in various cellular processes, including RNA splicing, transcription regulation, and RNA stability. Mislocalization and aggregation of TDP-43 in the cytoplasm are key features of the pathogenesis of several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer's disease (AD). This review provides a comprehensive retrospective and prospective analysis of TDP-43 research, highlighting structural insights, significant milestones, and the evolving understanding of its physiological and pathological functions. We delineate five major stages in TDP-43 research, from its initial discovery as a pathological hallmark in neurodegeneration to the recent advances in understanding its liquid-liquid phase separation (LLPS) behavior and interactions with cellular processes. Furthermore, we assess therapeutic strategies targeting TDP-43 pathology, categorizing approaches into direct and indirect interventions, alongside modulating aberrant TDP-43 LLPS. We propose that future research will focus on three critical areas: targeting TDP-43 structural polymorphisms for disease-specific therapeutics, exploring dual temporal-spatial modulation of TDP-43, and advancing nano-therapy. More importantly, we emphasize the importance of understanding TDP-43's functional repertoire at the mesoscale, which bridges its molecular functions with broader cellular processes. This review offers a foundational framework for advancing TDP-43 research and therapeutic development.},
}

@article {pmid40029926,
year = {2025},
author = {Panda, P and Mohanty, S and Gouda, SR and Baral, TC and Mohanty, A and Nayak, J and Mohapatra, R},
title = {Advanced strategies for enhancing the neuroprotective potential of curcumin: delivery systems and mechanistic insights in neurodegenerative disorders.},
journal = {Nutritional neuroscience},
volume = {},
number = {},
pages = {1-26},
doi = {10.1080/1028415X.2025.2472773},
pmid = {40029926},
issn = {1476-8305},
abstract = {Background: Curcumin, a polyphenolic compound derived from Curcuma longa, exhibits significant neuroprotective potential due to its diverse pharmacological properties.Objective: This review explores curcumin's role in modulating key pathological mechanisms underlying neurodegenerative disorders such as Alzheimer's, Parkinson's diseases, Amyotrophic Lateral Sclerosis, Huntington's Disease and Prion Disease.Methods: A comprehensive analysis of curcumin's molecular interactions, including its effects on amyloid-beta (Aβ) aggregation, tau hyperphosphorylation, neuroinflammation, oxidative stress, and metal-induced neurotoxicity, was conducted. Additionally, strategies to overcome its low bioavailability and blood-brain barrier (BBB) permeability were evaluated.Results: Curcumin inhibits Aβ aggregation and promotes disaggregation, reducing amyloid plaque formation in Alzheimer's disease. It modulates glial cell activity, attenuating neuroinflammation and fostering a neuroprotective environment. By interacting with tau proteins, curcumin prevents hyperphosphorylation and neurofibrillary tangle formation. As a potent antioxidant, it scavenges reactive oxygen species, mitigating oxidative stress-related neuronal damage. Its metal-chelating properties further diminish neurotoxicity by sequestering iron and copper ions. Despite its limited bioavailability and BBB permeability, curcumin's therapeutic efficacy can be enhanced using nanocarriers such as nanoparticles, liposomes, and micelles, which improve solubility, stability, and brain penetration.Conclusion: Curcumin's multifaceted neuroprotective mechanisms make it a promising candidate for preventing or slowing neurodegenerative disease progression. Advanced drug delivery systems hold potential for overcoming its pharmacokinetic limitations, paving the way for future clinical applications.},
}

@article {pmid40029669,
year = {2025},
author = {Carroll, E and Scaber, J and Huber, KVM and Brennan, PE and Thompson, AG and Turner, MR and Talbot, K},
title = {Drug repurposing in amyotrophic lateral sclerosis (ALS).},
journal = {Expert opinion on drug discovery},
volume = {20},
number = {4},
pages = {447-464},
pmid = {40029669},
issn = {1746-045X},
mesh = {*Drug Repositioning ; Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Animals ; *Drug Discovery/methods ; Translational Research, Biomedical/methods ; },
abstract = {INTRODUCTION: Identifying treatments that can alter the natural history of amyotrophic lateral sclerosis (ALS) is challenging. For years, drug discovery in ALS has relied upon traditional approaches with limited success. Drug repurposing, where clinically approved drugs are reevaluated for other indications, offers an alternative strategy that overcomes some of the challenges associated with de novo drug discovery.

AREAS COVERED: In this review, the authors discuss the challenge of drug discovery in ALS and examine the potential of drug repurposing for the identification of new effective treatments. The authors consider a range of approaches, from screening in experimental models to computational approaches, and outline some general principles for preclinical and clinical research to help bridge the translational gap. Literature was reviewed from original publications, press releases and clinical trials.

EXPERT OPINION: Despite remaining challenges, drug repurposing offers the opportunity to improve therapeutic options for ALS patients. Nevertheless, stringent preclinical research will be necessary to identify the most promising compounds together with innovative experimental medicine studies to bridge the translational gap. The authors further highlight the importance of combining expertise across academia, industry and wider stakeholders, which will be key in the successful delivery of repurposed therapies to the clinic.},
}

*Drug Repositioning
Humans
*Amyotrophic Lateral Sclerosis/drug therapy
Animals
*Drug Discovery/methods
Translational Research, Biomedical/methods

@article {pmid40024955,
year = {2025},
author = {Masood, S and Almas, MS and Hassan, SSU and Tahira, S and Fiaz, MH and Minhas, UEA and Zafar, HMQ and Masood, M},
title = {Safety and efficacy of arimoclomol in amyotrophic lateral sclerosis: a systematic review and meta-analysis.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {},
number = {},
pages = {},
pmid = {40024955},
issn = {1590-3478},
abstract = {OBJECTIVES: Amyotrophic Lateral Sclerosis (ALS) is a debilitating motor neuron disorder characterized by muscle weakness, atrophy, and spasticity. This meta-analysis aims to assess the safety and efficacy of Arimoclomol in patients with ALS.

METHOD: A comprehensive literature search was conducted on 3 databases to discover articles published up to August 2024. Included studies were randomized controlled trials (RCTs). Data was analysed using Review Manager (v5.4). Cochrane Risk of Bias-2 (RoB-2) was adopted to assess the quality of RCTs.

RESULTS: A total of 359 patients were analysed, with 239 individuals in the Arimoclomol group and 120 individuals in the placebo group. The pooled analysis of the primary outcome, change in Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) score from baseline, did not demonstrate a statistically significant difference favoring the Arimoclomol group (MD = 0.4495; 95% CI: -0.39, 1.27; p = 0.30). Similarly, secondary outcomes, including the Combined Assessment of Function and Survival (CAFS) rank score (MD = 1.00; 95% CI: -2.68, 4.67; p = 0.60), increase in transaminases (RR = 1.05; 95% CI: 0.19, 5.70; p = 0.95), mortality rate (RR = 0.86; 95% CI: 0.55, 1.34; p = 0.50), and adverse events (RR = 0.86; 95% CI: 0.55, 1.34; p = 0.50), showed no statistically significant differences between the groups.

CONCLUSION: This study does not conclusively demonstrate that Arimoclomol has beneficial effects on ALS patients' physical functionality but shows promise for safety. Further clinical trials are needed to explore the neuroprotective effects of Arimoclomol in the treatment of ALS.},
}

@article {pmid40017539,
year = {2025},
author = {Mengistu, DY and Terribili, M and Pellacani, C and Ciapponi, L and Marzullo, M},
title = {Epigenetic regulation of TDP-43: potential implications for amyotrophic lateral sclerosis.},
journal = {Frontiers in molecular medicine},
volume = {5},
number = {},
pages = {1530719},
pmid = {40017539},
issn = {2674-0095},
abstract = {Amyotrophic lateral sclerosis (ALS) is a multifactorial neurodegenerative disease characterized by the progressive degeneration of motor neurons. One of the key pathogenic factors implicated in ALS is TDP-43 (TAR DNA-binding protein 43), an RNA-binding protein encoded by the TARDBP gene. Under normal physiological conditions, TDP-43 predominantly resides in the nucleus, where it plays a critical role in regulating gene expression, alternative splicing, RNA transport, and stability. In ALS, TDP-43 undergoes pathological mislocalization from the nucleus to the cytoplasm, disrupting its normal function and contributing to disease progression. The nuclear loss of TDP-43 leads to widespread dysregulation of RNA metabolism. Moreover, mislocalized TDP-43 aggregates in the cytoplasm, acquires toxic properties that sequester essential RNA molecules and proteins. Importantly, deviations in TDP-43 levels, whether excessive or reduced, can lead to cellular dysfunction, and contribute to disease progression, highlighting the delicate balance required for neuronal health. Emerging evidence suggests that epigenetic mechanisms may play a crucial role in regulating TARDBP expression and, consequently, TDP-43 cellular levels. Epigenetic modifications such as DNA methylation, histone modifications, and non-coding RNAs are increasingly recognized as modulators of gene expression and cellular function in neurodegenerative diseases, including ALS. Dysregulation of these processes could contribute to aberrant TARDBP expression, amplifying TDP-43-associated pathologies. This review explores and summarizes the recent findings on how specific epigenetic modifications influence TDP-43 expression and discusses their possible implications for disease progression.},
}

@article {pmid40012994,
year = {2025},
author = {Sabetta, E and Ferrari, D and Massimo, L and Kõks, S},
title = {Tandem repeat expansions and copy number variations as risk factors and diagnostic tools for amyotrophic lateral sclerosis.},
journal = {Frontiers in neurology},
volume = {16},
number = {},
pages = {1522445},
pmid = {40012994},
issn = {1664-2295},
abstract = {Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disorder leading to upper and lower motoneurons degeneration. Although several mechanisms potentially involved in disease development have been identified, its pathogenesis is not fully understood. From the patient side, ALS diagnosis, still based on clinical criteria, can be difficult and may take up to 1 year. More than 30 genes have been associated to genetically inherited ALS, among which four (C9ORF72, SOD1, TARDBP and FUS) would explain around 60-70% of cases. However, familial ALS represents only 5-10% of ALS cases while the remaining are sporadic, with genetics explaining 6-10% of such cases only. In this context, short tandem repeats (STRs) expansions, have recently been found in clinically diagnosed ALS patients. In this review, we discuss the recent discoveries on ALS associated STRs and their potential as biomarkers as well as prognosis and therapy targets.},
}

@article {pmid40012862,
year = {2024},
author = {Tang, MB and Liu, YX and Hu, ZW and Luo, HY and Zhang, S and Shi, CH and Xu, YM},
title = {Study insights in the role of PGC-1α in neurological diseases: mechanisms and therapeutic potential.},
journal = {Frontiers in aging neuroscience},
volume = {16},
number = {},
pages = {1454735},
pmid = {40012862},
issn = {1663-4365},
abstract = {Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), which is highly expressed in the central nervous system, is known to be involved in the regulation of mitochondrial biosynthesis, metabolic regulation, neuroinflammation, autophagy, and oxidative stress. This knowledge indicates a potential role of PGC-1α in a wide range of functions associated with neurological diseases. There is emerging evidence indicating a protective role of PGC-1α in the pathogenesis of several neurological diseases. As such, a deeper and broader understanding of PGC-1α and its role in neurological diseases is urgently needed. The present review provides a relatively complete overview of the current knowledge on PGC-1α, including its functions in different types of neurons, basic structural characteristics, and its interacting transcription factors. Furthermore, we present the role of PGC-1α in the pathogenesis of various neurological diseases, such as intracerebral hemorrhage, ischemic stroke, Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, Huntington's disease, and other PolyQ diseases. Importantly, we discuss some compounds or drug-targeting strategies that have been studied to ameliorate the pathology of these neurological diseases and introduce the possible mechanistic pathways. Based on the available studies, we propose that targeting PGC-1α could serve as a promising novel therapeutic strategy for one or more neurological diseases.},
}

@article {pmid40012679,
year = {2025},
author = {Glashutter, M and Wijesinghe, P and Matsubara, JA},
title = {TDP-43 as a potential retinal biomarker for neurodegenerative diseases.},
journal = {Frontiers in neuroscience},
volume = {19},
number = {},
pages = {1533045},
pmid = {40012679},
issn = {1662-4548},
abstract = {TDP-43 proteinopathies are a spectrum of neurodegenerative diseases (NDDs) characterized by the pathological cytoplasmic aggregation of the TDP-43 protein. These include amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), Alzheimer's disease (AD), chronic traumatic encephalopathy (CTE), and others. TDP-43 in the eye shows promise as a biomarker for these NDDs. Several studies have identified cytoplasmic TDP-43 inclusions in retinal layers of donors with ALS, FTLD, AD, CTE, and other conditions using immunohistochemistry. Our findings suggest that pathological aggregates of TDP-43 in the human retina are most prevalent in FTLD-TDP, ALS, and CTE, suggesting these diseases may provide the most reliable context for studying the potential of TDP-43 as a retinal biomarker. Animal model studies have been pivotal in exploring TDP-43's roles in the retina, including its nuclear and cytoplasmic localization, RNA binding properties, and interactions with other proteins. Despite these advances, more research is needed to develop therapeutic strategies. A major limitation of human autopsy studies is the lack of corresponding brain pathology assessments to confirm TDP-43 proteinopathy diagnosis and staging. Other limitations include small sample sizes, lack of antemortem eye pathology and clinical histories, and limited comparisons across multiple NDDs. Future directions for the TDP-43 as a retinal biomarker for NDDs include retinal tracers, hyperspectral imaging, oculomics, and machine learning development.},
}

@article {pmid40012174,
year = {2025},
author = {Rajamanickam, G and Hu, Z and Liao, P},
title = {Targeting the TRPM4 Channel for Neurologic Diseases: Opportunity and Challenge.},
journal = {The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry},
volume = {},
number = {},
pages = {10738584251318979},
doi = {10.1177/10738584251318979},
pmid = {40012174},
issn = {1089-4098},
abstract = {As a monovalent cation channel, the transient receptor potential melastatin 4 (TRPM4) channel is a unique member of the transient receptor potential family. Abnormal TRPM4 activity has been identified in various neurologic disorders, such as stroke, spinal cord injury, traumatic brain injury, multiple sclerosis, amyotrophic lateral sclerosis, pathologic pain, and epilepsy. Following brain hypoxia/ischemia and inflammation, TRPM4 up-regulation and enhanced activity contribute to the cell death of neurons, vascular endothelial cells, and astrocytes. Enhanced ionic influx via TRPM4 leads to cell volume increase and oncosis. Depolarization of membrane potential following TRPM4 activation and interaction between TRPM4 and N-methyl-d-aspartate receptors exacerbate excitotoxicity during hypoxia. Importantly, TRPM4 expression and activity remain low in healthy neurons, making it an ideal drug target. Current approaches to inhibit or modulate the TRPM4 channel have various limitations that hamper the interpretation of TRPM4 physiology in the nervous system and potentially hinder their translation into therapy. In this review, we discuss the pathophysiologic roles of TRPM4 and the different inhibitors that modulate TRPM4 activity for potential treatment of neurologic diseases.},
}

@article {pmid40009859,
year = {2025},
author = {Chung, J and Lim, F},
title = {Effect of Nurse Residency Programs on New Graduate Nurses Entering the Critical Care Setting: An Integrative Review.},
journal = {Critical care nursing quarterly},
volume = {48},
number = {2},
pages = {120-142},
pmid = {40009859},
issn = {1550-5111},
mesh = {Humans ; *Clinical Competence ; *Critical Care Nursing/education ; *Preceptorship ; Education, Nursing, Baccalaureate ; Critical Care ; Internship, Nonmedical/organization & administration ; },
abstract = {The transition period from undergraduate nursing education to professional practice is a time of uncertainty and great difficulty for new graduate nurses (NGNs). Nurse residency programs (NRPs) provide structured education, simulation-based learning, and preceptorship to ease the transition. Although its effect on improving retention of NGNs is well established in the literature, the effect on clinical competency has not been documented as well. The purpose of this integrative review is to appraise the available literature and synthesize the evidence that demonstrates the effect of NRPs on clinical competency of NGNs entering the critical care setting. Inclusion criteria were quantitative and qualitative studies, peer-reviewed studies published after 2004 and in English, identified through a systematic literature search using the CINAHL database. Critical appraisal of the articles was completed using Law et al's Critical Review Form. Eight articles (4 quantitative, 3 mixed method, and 1 qualitative study) met the inclusion criteria. The themes identified were common tools used to assess the efficacy of NRPs, improved clinical competency of NGNs, improved self-confidence, improved retention rates, and peer support among NGNs. Implications for nursing education and practice include applying evidence-based NRPs, incorporating simulation, enhancing sustainability, and reducing NRP variability through accreditation.},
}

Humans
*Clinical Competence
*Critical Care Nursing/education
*Preceptorship
Education, Nursing, Baccalaureate
Critical Care
Internship, Nonmedical/organization & administration

@article {pmid40009238,
year = {2025},
author = {Ruffo, P and Traynor, BJ and Conforti, FL},
title = {Advancements in genetic research and RNA therapy strategies for amyotrophic lateral sclerosis (ALS): current progress and future prospects.},
journal = {Journal of neurology},
volume = {272},
number = {3},
pages = {233},
pmid = {40009238},
issn = {1432-1459},
support = {ZIA AG000933/ImNIH/Intramural NIH HHS/United States ; },
mesh = {*Amyotrophic Lateral Sclerosis/genetics/therapy/diagnosis ; Humans ; Genetic Therapy/methods ; },
abstract = {This review explores the intricate landscape of neurodegenerative disease research, focusing on Amyotrophic Lateral Sclerosis (ALS) and the intersection of genetics and RNA biology to investigate the causative pathogenetic basis of this fatal disease. ALS is a severe neurodegenerative disease characterized by the progressive loss of motor neurons, leading to muscle weakness and paralysis. Despite significant research advances, the exact cause of ALS remains largely unknown. Thanks to the application of next-generation sequencing (NGS) approaches, it was possible to highlight the fundamental role of rare variants with large effect sizes and involvement of portions of non-coding RNA, providing valuable information on risk prediction, diagnosis, and treatment of age-related diseases, such as ALS. Genetic research has provided valuable insights into the pathophysiology of ALS, leading to the development of targeted therapies such as antisense oligonucleotides (ASOs). Regulatory agencies in several countries are evaluating the commercialization of Qalsody (Tofersen) for SOD1-associated ALS, highlighting the potential of gene-targeted therapies. Furthermore, the emerging significance of microRNAs (miRNAs) and long RNAs are of great interest. MiRNAs have emerged as promising biomarkers for diagnosing ALS and monitoring disease progression. Understanding the role of lncRNAs in the pathogenesis of ALS opens new avenues for therapeutic intervention. However, challenges remain in delivering RNA-based therapeutics to the central nervous system. Advances in genetic screening and personalized medicine hold promise for improving the management of ALS. Ongoing clinical trials use genomic approaches for patient stratification and drug targeting. Further research into the role of non-coding RNAs in the pathogenesis of ALS and their potential as therapeutic targets is crucial to the development of effective treatments for this devastating disease.},
}

*Amyotrophic Lateral Sclerosis/genetics/therapy/diagnosis
Humans
Genetic Therapy/methods

@article {pmid40006958,
year = {2025},
author = {Mielcarska, MB and Rouse, BT},
title = {Viruses and the Brain-A Relationship Prone to Trouble.},
journal = {Viruses},
volume = {17},
number = {2},
pages = {},
pmid = {40006958},
issn = {1999-4915},
mesh = {Humans ; *Brain/virology ; Animals ; Viruses/pathogenicity/genetics ; Antiviral Agents/therapeutic use/pharmacology ; Virus Diseases/virology ; Neurodegenerative Diseases/virology ; },
abstract = {Neurological disorders, some of which are associated with viral infections, are growing due to the aging and expanding population. Despite strong defenses of the central nervous system, some viruses have evolved ways to breach them, which often result in dire consequences. In this review, we recount the various ways by which different viruses can enter the CNS, and we describe the consequences of such invasions. Consequences may manifest as acute disease, such as encephalitis, meningitis, or result in long-term effects, such as neuromuscular dysfunction, as occurs in poliomyelitis. We discuss evidence for viral involvement in the causation of well-known chronic neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, as well as vascular dementia in the elderly. We also describe the approaches currently available to control a few of the neural viral infections. These include antivirals that are effective against human immunodeficiency virus and herpes simplex virus, as well as vaccines valuable for controlling rabies virus, poliomyelitis virus, and some flavivirus infections. There is an urgent need to better understand, at a molecular level, how viruses contribute to acute and, especially, chronic neurological diseases and to develop more precise and effective vaccines and therapies.},
}

Humans
*Brain/virology
Animals
Viruses/pathogenicity/genetics
Antiviral Agents/therapeutic use/pharmacology
Virus Diseases/virology
Neurodegenerative Diseases/virology

@article {pmid40004464,
year = {2025},
author = {Liu, Z and Song, SY},
title = {Genomic and Transcriptomic Approaches Advance the Diagnosis and Prognosis of Neurodegenerative Diseases.},
journal = {Genes},
volume = {16},
number = {2},
pages = {},
pmid = {40004464},
issn = {2073-4425},
mesh = {Humans ; *Neurodegenerative Diseases/genetics/diagnosis ; *Transcriptome/genetics ; Prognosis ; *Genome-Wide Association Study/methods ; Genomics/methods ; Gene Expression Profiling/methods ; Amyotrophic Lateral Sclerosis/genetics/diagnosis ; Genetic Predisposition to Disease ; },
abstract = {Neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), represent a growing societal challenge due to their irreversible progression and significant impact on patients, caregivers, and healthcare systems. Despite advances in clinical and imaging-based diagnostics, these diseases are often detected at advanced stages, limiting the effectiveness of therapeutic interventions. Recent breakthroughs in genomic and transcriptomic technologies, including whole-genome sequencing, single-cell RNA sequencing (scRNA-seq), and CRISPR-based screens, have revolutionized the field, offering new avenues for early diagnosis and personalized prognosis. Genomic approaches have elucidated disease-specific genetic risk factors and molecular pathways, while transcriptomic studies have identified stage-specific biomarkers that correlate with disease progression and severity. Furthermore, genome-wide association studies (GWAS), polygenic risk scores (PRS), and spatial transcriptomics are enabling the stratification of patients based on their risk profiles and prognostic trajectories. Advances in functional genomics have uncovered actionable targets, such as ATXN2 in ALS and TREM2 in AD, paving the way for tailored therapeutic strategies. Despite these achievements, challenges remain in translating genomic discoveries into clinical practice due to disease heterogeneity and the complexity of neurodegenerative pathophysiology. Future integration of genetic technologies holds promise for transforming diagnostic and prognostic paradigms, offering hope for improved patient outcomes and precision medicine approaches.},
}

Humans
*Neurodegenerative Diseases/genetics/diagnosis
*Transcriptome/genetics
Prognosis
*Genome-Wide Association Study/methods
Genomics/methods
Gene Expression Profiling/methods
Amyotrophic Lateral Sclerosis/genetics/diagnosis
Genetic Predisposition to Disease

@article {pmid40004056,
year = {2025},
author = {Yan, B and Suen, MC and Xu, N and Lu, C and Liu, C and Zhu, G},
title = {G-Quadruplex Structures Formed by Human Telomere and C9orf72 GGGGCC Repeats.},
journal = {International journal of molecular sciences},
volume = {26},
number = {4},
pages = {},
pmid = {40004056},
issn = {1422-0067},
support = {32071188//National Scientific Foundation of China/ ; 16101120, 161011121, AoE/M-403-16, AoE/M-401/20//Research Grants Council of the Hong Kong Special Administrative Region, China/ ; BGF.2023.019//Hong Kong University of Science and Technology, China/ ; 2021A1515220104//Guangdong Basic and Applied Basic Research Foundation, China/ ; 32301012//Young Scientists Fund of the National Natural Science Foundation of China/ ; },
mesh = {*G-Quadruplexes ; Humans ; *Telomere/genetics ; *C9orf72 Protein/genetics ; *DNA Repeat Expansion/genetics ; *Amyotrophic Lateral Sclerosis/genetics ; Frontotemporal Dementia/genetics/pathology ; },
abstract = {G-quadruplexes (G4s) are unique nucleic acid structures composed of guanine-rich (G-rich) sequences that can form diverse topologies based on the arrangement of their four strands. G4s have attracted attention for their potential roles in various biological processes and human diseases. In this review, we focus on the G4 structures formed by human telomeric sequences, (GGGTTA)n, and the hexanucleotide repeat expansion, (GGGGCC)n, in the first intron region of the chromosome 9 open reading frame 72 (C9orf72) gene, highlighting their structural diversity and biological significance. Human telomeric G4s play crucial roles in telomere retention and gene regulation. In particular, we provide an in-depth summary of known telomeric G4s and focus on our recently discovered chair-type conformation, which exhibits distinct folding patterns. The chair-type G4s represent a novel folding pattern with unique characteristics, expanding our knowledge of telomeric G4 structural diversity and potential biological functions. Specifically, we emphasize the G4s formed by the (GGGGCC)n sequence of the C9orf72 gene, which represents the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The thorough structural analysis in this review advances our comprehension of the disease mechanism and provides valuable insights into developing targeted therapeutic strategies in ALS/FTD.},
}

*G-Quadruplexes
Humans
*Telomere/genetics
*C9orf72 Protein/genetics
*DNA Repeat Expansion/genetics
*Amyotrophic Lateral Sclerosis/genetics
Frontotemporal Dementia/genetics/pathology

@article {pmid40002740,
year = {2025},
author = {Meng, K and Jia, H and Hou, X and Zhu, Z and Lu, Y and Feng, Y and Feng, J and Xia, Y and Tan, R and Cui, F and Yuan, J},
title = {Mitochondrial Dysfunction in Neurodegenerative Diseases: Mechanisms and Corresponding Therapeutic Strategies.},
journal = {Biomedicines},
volume = {13},
number = {2},
pages = {},
pmid = {40002740},
issn = {2227-9059},
support = {600791001//the Research Start-up Fund of Jining Medical University/ ; JYHL2021MS13//Research Fund for Lin He's Academician Workstation of New Medicine and Clinical Translation in Jining Medical University/ ; 81700055//the National Natural Science Foundation of China/ ; Grant No. D2016021//Outstanding Talent Research Funding of Xuzhou Medical University/ ; BK20160229//Natural Science Foundation of Jiangsu Province/ ; tsqn201909147//Taishan Scholars Program of Shandong Province/ ; G2Y-kJS-SD-2023-097//Co-construction of Science and Technology Projects by the Science and Technology Department of the State Administration of Traditional Chinese Medicine/ ; },
abstract = {Neurodegenerative disease (ND) refers to the progressive loss and morphological abnormalities of neurons in the central nervous system (CNS) or peripheral nervous system (PNS). Examples of neurodegenerative diseases include Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Recent studies have shown that mitochondria play a broad role in cell signaling, immune response, and metabolic regulation. For example, mitochondrial dysfunction is closely associated with the onset and progression of a variety of diseases, including ND, cardiovascular diseases, diabetes, and cancer. The dysfunction of energy metabolism, imbalance of mitochondrial dynamics, or abnormal mitophagy can lead to the imbalance of mitochondrial homeostasis, which can induce pathological reactions such as oxidative stress, apoptosis, and inflammation, damage the nervous system, and participate in the occurrence and development of degenerative nervous system diseases such as AD, PD, and ALS. In this paper, the latest research progress of this subject is detailed. The mechanisms of oxidative stress, mitochondrial homeostasis, and mitophagy-mediated ND are reviewed from the perspectives of β-amyloid (Aβ) accumulation, dopamine neuron damage, and superoxide dismutase 1 (SOD1) mutation. Based on the mechanism research, new ideas and methods for the treatment and prevention of ND are proposed.},
}

@article {pmid40002527,
year = {2025},
author = {Eisen, A and Kiernan, MC},
title = {The Neonatal Microbiome: Implications for Amyotrophic Lateral Sclerosis and Other Neurodegenerations.},
journal = {Brain sciences},
volume = {15},
number = {2},
pages = {},
pmid = {40002527},
issn = {2076-3425},
abstract = {Most brain development occurs in the "first 1000 days", a critical period from conception to a child's second birthday. Critical brain processes that occur during this time include synaptogenesis, myelination, neural pruning, and the formation of functioning neuronal circuits. Perturbations during the first 1000 days likely contribute to later-life neurodegenerative disease, including sporadic amyotrophic lateral sclerosis (ALS). Neurodevelopment is determined by many events, including the maturation and colonization of the infant microbiome and its metabolites, specifically neurotransmitters, immune modulators, vitamins, and short-chain fatty acids. Successful microbiome maturation and gut-brain axis function depend on maternal factors (stress and exposure to toxins during pregnancy), mode of delivery, quality of the postnatal environment, diet after weaning from breast milk, and nutritional deficiencies. While the neonatal microbiome is highly plastic, it remains prone to dysbiosis which, once established, may persist into adulthood, thereby inducing the development of chronic inflammation and abnormal excitatory/inhibitory balance, resulting in neural excitation. Both are recognized as key pathophysiological processes in the development of ALS.},
}