Molecular Neurodegeneration最新文献

{"title":"Mutations in PSEN1 predispose inflammation in an astrocyte model of familial Alzheimer’s disease through disrupted regulated intramembrane proteolysis","authors":"Oliver J. Ziff, Gustavo Morrone Parfitt, Sarah Jolly, Jackie M. Casey, Lucy Granat, Satinder Samra, Núria Setó-Salvia, Argyro Alatza, Leela Phadke, Benjamin Galet, Philippe Ravassard, Marie-Claude Potier, John Hardy, Dervis A. Salih, Paul Whiting, Fiona Ducotterd, Rickie Patani, Selina Wray, Charles Arber","doi":"10.1186/s13024-025-00864-7","DOIUrl":"https://doi.org/10.1186/s13024-025-00864-7","url":null,"abstract":"Mutations in PSEN1 cause familial Alzheimer’s disease with almost complete penetrance. Age at onset is highly variable between different PSEN1 mutations and even within families with the same mutation. Current research into late onset Alzheimer’s disease implicates inflammation in both disease onset and progression. PSEN1 is the catalytic subunit of γ-secretase, responsible for regulated intramembrane proteolysis of numerous substrates that include cytokine receptors. For this reason, we tested the hypothesis that mutations in PSEN1 impact inflammatory responses in astrocytes, thereby contributing to disease progression. We developed patient-derived models of iPSC-astrocytes, representing three lines harbouring PSEN1 mutations and six control lines (including two isogenic controls). Transcriptomic and biochemical assays were used to investigate differential inflammatory responses to TNFα, IL1α and C1Q. We show that PSEN1 is upregulated in response to inflammatory stimuli, and this upregulation is disrupted by pathological PSEN1 mutations. Using transcriptomic analyses, we demonstrate that PSEN1 mutant astrocytes have an augmented inflammatory profile in their basal state, concomitant with gene expression signatures revealing dysregulated intramembrane proteolysis and JAK-STAT signalling. Detailed investigation of the JAK-STAT2 signalling pathway showed reduced cell surface expression of IFNAR2, lower STAT2 phosphorylation cascades and delayed NFκB nuclear localisation in PSEN1 mutant astrocytes in response to inflammatory stimuli, thereby implicating the notion of altered cytokine signalling cascades. Finally, we use small molecule modulators of γ-secretase to confirm a role for PSEN1/γ-secretase in regulating the astrocytic response to inflammatory stimuli. Together, these data suggest that mutations in PSEN1 enhance cytokine signalling via impaired regulated intramembrane proteolysis, thereby predisposing astrocytic inflammatory profiles. These findings support a two-hit contribution of PSEN1 mutations to fAD pathogenesis, not only impacting APP and Aβ processing but also altering the cellular response to inflammation.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"48 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144335014","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical progression and genetic pathways in body-first and brain-first Parkinson’s disease","authors":"Massimiliano Passaretti, Daniel Veréb, Mite Mijalkov, Yu-Wei Chang, Hang Zhao, Blanca Zufiria-Gerbolés, Jiawei Sun, Giovanni Volpe, Natalia Rivera, Matteo Bologna, Joana B. Pereira","doi":"10.1186/s13024-025-00866-5","DOIUrl":"https://doi.org/10.1186/s13024-025-00866-5","url":null,"abstract":"Parkinson’s disease (PD) is a highly heterogeneous disorder with distinct phenotypes that can develop well before motor symptoms appear. Recently, two main phenotypes based on the different pathological spreading patterns of PD have been proposed: “body-first”, where α-synuclein pathology begins in the peripheral nervous system and spreads symmetrically from bottom-up, and “brain-first”, where pathology starts in the brain and spreads asymmetrically downwards. However, no studies have assessed these phenotypes across both prodromal and clinical PD stages, tracked their pathological progression in vivo or identified potential underlying biological mechanisms. To address this, we analyzed 910 prodromal and 1120 clinical PD cases with comprehensive longitudinal clinical, imaging, and genetic data from the Parkinson Progression Marker Initiative over a 12-year period. Our findings revealed that both prodromal and clinical groups with body-first symptoms exhibited greater motor dysfunction, anxiety, and depression at baseline; as well as worse longitudinal motor progression and attention decline compared to brain-first cases. The body-first and brain-first phenotypes were stable over time and predicted conversion to clinical PD in prodromal cases, and were also found using unsupervised deep learning analyses. Additionally, body-first cases displayed more pronounced changes in the caudal LC, as well as symmetrical alterations in the striatum and glymphatic system, consistent with the traditional bottom-up progression described by Braak’s staging of α-synuclein pathology and the more symmetric distribution proposed for body-first PD. In contrast, brain-first cases exhibited changes in the rostral LC and asymmetric alterations in the striatum and glymphatic system, suggesting a top-down progression. Genetic analysis also identified new specific single nucleotide polymorphisms associated with PD phenotypes, such as TRIM40 and IP6K2, linked to worse motor and cognitive outcomes in prodromal cases. These findings emphasize the importance of recognizing body-first and brain-first PD as distinct entities with unique clinical, imaging, and genetic profiles, paving the way for targeted and personalized therapeutic strategies that address the specific pathophysiological mechanisms of PD.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"25 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144334913","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"sPLA2-IIA modifies progranulin deficiency phenotypes in mouse models","authors":"Cha Yang, Huan Du, Gwang Bin Lee, Masaaki Uematsu, Weiguo He, Etienne Doré, Weizhi Yu, Ethan J. Sanford, Marcus B. Smolka, Eric Boilard, Jeremy M. Baskin, Ling Hao, Fenghua Hu","doi":"10.1186/s13024-025-00863-8","DOIUrl":"https://doi.org/10.1186/s13024-025-00863-8","url":null,"abstract":"Haploinsufficiency of the progranulin (PGRN) protein is a leading cause of frontotemporal lobar degeneration (FTLD). Mouse models have been developed to study PGRN functions. However, PGRN deficiency in the commonly used C57BL/6 mouse strain background leads to very mild phenotypes, and pathways regulating PGRN deficiency phenotypes remain to be elucidated. We generated PGRN-deficient mice in the FVB/N background and compared PGRN deficiency phenotypes between C57BL/6 and FVB/N backgrounds via immunostaining, western blot, RNA-seq, and proteomics approaches. We demonstrated a novel pathway in modifying PGRN deficiency phenotypes using inhibitor treatment and AAV-mediated overexpression in mouse models. We report that PGRN loss in the FVB/N mouse strain results in earlier onset and stronger FTLD-related and lysosome-related phenotypes. We found that PGRN interacts with sPLA2-IIA, a member of the secreted phospholipase A2 (sPLA2) family member and a key regulator of inflammation, that is expressed in FVB/N but not C57BL/6 background. sPLA2-IIA inhibition rescues PGRN deficiency phenotypes, while sPLA2-IIA overexpression drives enhanced gliosis and lipofuscin accumulation in PGRN-deficient mice. Additionally, RNA-seq and proteomics analysis revealed that mitochondrial pathways are upregulated in the PGRN-deficient C57BL/6 mice but not in the FVB/N mice. Our studies establish a better mouse model for FTLD-GRN and uncover novel pathways modifying PGRN deficiency phenotypes.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"4 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144304630","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In Memoriam of Edward H. Koo, MD 1954-2025.","authors":"Hui Zheng,Douglas Galasko,Sangram S Sisodia","doi":"10.1186/s13024-025-00862-9","DOIUrl":"https://doi.org/10.1186/s13024-025-00862-9","url":null,"abstract":"","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"6 1","pages":"70"},"PeriodicalIF":15.1,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144295665","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Interrogating the plasma proteome of repetitive head impact exposure and chronic traumatic encephalopathy","authors":"Rowan Saloner, Kaitlin B. Casaletto, Sruti Rayaprolu, Louisa Cornelis, Paramita Chakrabarty, Jose F. Abisambra, Salvatore Spina, Lea T. Grinberg, William W. Seeley, Bruce L. Miller, Joel H. Kramer, Gil D. Rabinovici, Breton M. Asken","doi":"10.1186/s13024-025-00860-x","DOIUrl":"https://doi.org/10.1186/s13024-025-00860-x","url":null,"abstract":"Exposure to repetitive head impacts (RHI) is associated with increased risk for chronic traumatic encephalopathy (CTE), a neurodegenerative tauopathy, and other neuropathological changes. Biological drivers of RHI-related neurodegeneration are not well understood. We interrogated the plasma proteome in aging adults with prior RHI compared to healthy controls (CTL) and individuals with Alzheimer’s disease (AD), including a subset characterized neuropathologically at autopsy. Proximity extension assay (Olink Explore®) quantified 2,779 plasma proteins in 22 RHI patients (all AD-biomarker negative), 39 biomarker-confirmed AD, and 44 CTL. A subset of participants went to autopsy (N = 16) allowing for comparisons of the antemortem plasma proteome between autopsy-confirmed CTE + (N = 7) and CTE- (N = 9). Differential abundance and co-expression network analyses identified plasma proteomic signatures of RHI, which were functionally annotated using gene ontology and cell type enrichment analysis. Nonparametric correlations examined plasma proteomic associations with orthogonally-measured plasma biomarkers, global cognitive function, and semi-quantitative ratings of neuropathology burden at autopsy. Differential abundance analysis revealed 434 increased (vs. 6 decreased) proteins in RHI vs. CTL and 193 increased (vs. 14 decreased) in RHI vs. AD. Network analysis identified 9 protein co-expression modules (M1-M9), of which 7 were elevated in RHI compared to AD or CTL. Modules with increased abundance in RHI were enriched for mitochondrial/metabolic, cell division, and immunovascular (e.g., cell adhesion, TNF-signaling) processes. RHI-related modules exhibited strong and selective correlations with immunoassay-based plasma IL-6 in RHI cases, including the M2 TNF-signaling/cell adhesion module which harbored proteins that strongly tracked with cognitive function. RHI-related plasma protein signatures were similar in the subset of participants with autopsy-confirmed CTE, including immune and metabolic modules that positively correlated with medial temporal lobe tau and TDP-43 burden. Molecular pathways in plasma most consistently implicated in RHI were tied to immune response, mitochondrial function, and cell metabolism. RHI-related proteomic signatures tracked with antemortem cognitive severity and postmortem neuropathological burden, providing converging evidence for their role in disease progression. Differentially abundant proteins and co-expression modules in RHI may inform mechanisms linking RHI to increased dementia risk, thus guiding diagnostic biomarker and therapeutic development for at-risk populations.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"10 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144296200","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Myelin dysfunction in aging and brain disorders: mechanisms and therapeutic opportunities.","authors":"Zhihai Huang,Yulan Zhang,Peibin Zou,Xuemei Zong,Quanguang Zhang","doi":"10.1186/s13024-025-00861-w","DOIUrl":"https://doi.org/10.1186/s13024-025-00861-w","url":null,"abstract":"Myelin is a multilamellar membrane that surrounds axons in the vertebrate nervous system. Properly functioning myelin is essential for the rapid conduction of nerve impulses, and it metabolically supports axonal integrity. Emerging evidence indicates that myelin is also involved in various aspects of cognition, with adaptive myelination playing a critical role in memory consolidation and motor learning. However, these physiological processes can be disrupted in various diseases. Understanding the mechanisms underlying myelin pathology is therefore essential for the development of targeted therapies for associated medical conditions. This review provides a comprehensive overview of the role of myelin in neural function, with a particular focus on adaptive myelination in cognition. We also highlight myelin dysfunction and the underlying mechanisms in the aging brain, as well as in diverse brain disorders and neurological conditions, including neurodegenerative diseases, psychiatric conditions, brain injuries, chemotherapy-related cognitive impairment, and neurological symptoms associated with COVID-19. Furthermore, we discuss the therapeutic potential of recently identified pro-myelinating compounds in aging-associated cognitive decline and brain disorders, as well as the future of remyelination therapies. Current evidence suggests that restoring functional myelin may serve as a therapeutic strategy for various medical conditions associated with myelin dysfunction.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"22 1","pages":"69"},"PeriodicalIF":15.1,"publicationDate":"2025-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144295700","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Extracellular vesicles in TDP-43 proteinopathies: pathogenesis and biomarker potential","authors":"Elizabeth R. Dellar, Lara Nikel, Stephanie Fowler, Björn F. Vahsen, Ruxandra Dafinca, Emily Feneberg, Kevin Talbot, Martin R. Turner, Alexander G. Thompson","doi":"10.1186/s13024-025-00859-4","DOIUrl":"https://doi.org/10.1186/s13024-025-00859-4","url":null,"abstract":"Extracellular vesicles (EVs) are membrane-enclosed nanoparticles released by most cell types, and from multiple sub-cellular compartments. They carry a range of cargo biomolecules, including protein and RNA that reflect the type and status of their cell of origin. EVs are associated with the 43 kDa trans-active response DNA binding protein (TDP-43), aggregates of which are a key pathological feature across the spectrum of amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and other TDP-43 proteinopathies. The secretion of TDP-43 via EVs may have beneficial effects through the cellular clearance of aggregated protein, or detrimental effects via the intercellular spread of templated TDP-43 aggregation. This review examines evidence for the association of TDP-43 with EVs in post mortem tissue, in vitro models and human biofluids, and discusses evidence for EV TDP-43 involvement in pathogenesis via clearance or ‘seeding’ processes. We further discuss the potential for use of EVs in biomarker development, through analysis of TDP-43 or alternative protein and RNA cargoes. ","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"7 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144252078","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The many connections of UFMylation with Alzheimer’s disease: a comprehensive review","authors":"Tingxiang Yan, Benjamin D. Clarkson, Zhenkun Lou, Wolfdieter Springer, Fabienne C. Fiesel","doi":"10.1186/s13024-025-00855-8","DOIUrl":"https://doi.org/10.1186/s13024-025-00855-8","url":null,"abstract":"Alzheimer’s disease (AD) is a complex neurodegenerative disorder that is characterized by the accumulation of pathologic tau and beta-amyloid proteins. UFMylation is an emerging ubiquitin-like post-translational modification that is crucial for healthy brain development. The UFM1 cascade was recently identified as a major modifier of tau aggregation in vitro and in vivo. Moreover, post-mortem AD brain shows pronounced alterations of UFMylation that are significantly associated with pathological tau, suggesting UFM1 might indeed be a modifier of human disease. However, the link between AD and UFMylation is yet to be fully explored. Interestingly, the UFMylation cascade is known to play important roles for several pathways that are known to be altered in AD, such as the DNA damage response, ER homeostasis, autophagy and the immune response. This review discusses the many connections between UFMylation with AD pathogenesis, emphasizing the role of UFMylation in these pathways and their abnormalities in AD. Understanding these connections is important to elucidate molecular mechanisms how UFM1 may impact AD and to uncover novel therapeutic strategies targeting UFMylation pathways for disease modification.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"38 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144211184","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The UNC5C T835M mutation associated with Alzheimer’s disease leads to neurodegeneration involving oxidative stress and hippocampal atrophy in aged mice","authors":"Devi Krishna Priya Karunakaran, Makenna Ley, Joanna Guo, Ammaarah Khatri, Katherine Sadleir, Jelena Popovic, Arun Kumar Upadhyay, Jeffrey Savas, Daniele Procissi, Jasvinder Atwal, Robert Vassar","doi":"10.1186/s13024-025-00850-z","DOIUrl":"https://doi.org/10.1186/s13024-025-00850-z","url":null,"abstract":"Alzheimer’s disease (AD) is characterized by amyloid plaques, neurofibrillary tangles, and synaptic and neuronal loss. Recently, a rare autosomal dominant coding mutation, T835M, in the Un-coordinated 5c (UNC5C) netrin receptor gene was segregated with late-onset AD (LOAD). Overexpression of T835M in primary hippocampal neurons increased cell death in response to neurotoxic stimuli including beta-amyloid (Aβ) suggesting a mechanism by which T835M may confer increased risk of LOAD. However, the molecular mechanism of T835M-mediated cell death remained under explored. Toward this end, we generated a mouse T835M knock-in (Unc5cKI/KI) model and employed biochemical and histological analyses to understand the molecular mechanism of T835M-mediated pathogenesis in late onset Alzheimer's disease. We show that homozygous KI mice have significantly reduced hippocampal volume, increased ventricular volume, dendritic disorganization (CA1 region) and reduced UNC5C protein level by 12–18 months of age. Further, we show that the neuronal cell death is observed in the Unc5cKI/KI mice by 12 months of age by TUNEL analysis and activated Caspase 3/7 assay. Proteomic analysis of hippocampal samples showed upregulation of oxidative stress and downregulation of chaperone proteins at 18 months corroborating the biochemical and histological results showing increased c-Jun N-terminal Kinase (JNK) phosphorylation, NADPH oxidase, and decreased Netrin1 levels. Moreover, Unc5cKI/KI mice also show morphological changes in the astrocytes with increased number of branched processes, reduced GFAP levels, and significantly increased activation of microglia. Overall, these results suggest that T835M mutation causes neurodegeneration by creating an oxidative stress environment leading to synaptic degeneration and weakened astrocytes, thereby leading to neuronal cell death via apoptosis. Furthermore, to assess the effects of amyloid pathology on the mutation, we crossed Unc5cKI/KI mice with AppNL−G−F/NL−G−F mice and observed an exacerbation of mutation-associated changes along with increased levels of Aβ42, suggesting that the T835M mutation increases the susceptibility of neurons to cell death and elevated Aβ42 levels, thus promoting AD pathogenesis. Understanding the molecular mechanism of cell death in regions susceptible to neurodegeneration such as the hippocampus could shed light on the players and pathways involved in cell death in AD pathogenesis and therefore could inform therapeutic approaches for AD.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"260 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144211185","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RNA-binding proteins in ALS and FTD: from pathogenic mechanisms to therapeutic insights","authors":"Jens Rummens, Sandrine Da Cruz","doi":"10.1186/s13024-025-00851-y","DOIUrl":"https://doi.org/10.1186/s13024-025-00851-y","url":null,"abstract":"Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are devastating neurodegenerative disorders with overlapping clinical, genetic and pathological features. A large body of evidence highlights the critical role of RNA-binding proteins (RBPs) – in particular TAR DNA-binding protein 43 (TDP-43) and Fused in sarcoma (FUS) – in the pathogenesis of these diseases. These RBPs normally regulate various key aspects of RNA metabolism in the nervous system (by assembling into transient biomolecular condensates), but undergo cytoplasmic mislocalization and pathological aggregation in ALS and FTD. Furthermore, emerging evidence suggests that RBP-containing aggregates may propagate through the nervous system in a prion-like manner, driving the progression of these neurodegenerative diseases. In this review, we summarize the genetic and neuropathological findings that establish RBP dysfunction as a central theme in ALS and FTD, and discuss the role of disease-associated RBPs in health and disease. Furthermore, we review emerging evidence regarding the prion-like properties of RBP pathology, and explore the downstream mechanisms that drive neurodegeneration. By unraveling the complex role of RBPs in ALS and FTD, we ultimately aim to provide insights into potential avenues for therapeutic intervention in these incurable disorders.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"45 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144211188","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}