Translational Neurodegeneration最新文献

{"title":"Capsaicin suppresses microglial inflammation through TRPV1-SSR4 interaction.","authors":"Yifei Hou, Sichen Wang, Yuzhang Yang, Zhenzhen Zhao, Yuanyuan Xie, Xiaoyan Ouyang, Kaihua Zhang, Hongzhuan Chen, Jianrong Xu","doi":"10.1186/s40035-026-00589-7","DOIUrl":"10.1186/s40035-026-00589-7","url":null,"abstract":"<p><strong>Background: </strong>Transient receptor potential vanilloid 1 (TRPV1) is increasingly recognized as an important regulator of microglial response during neuroinflammation, a key pathological feature of various neurodegenerative diseases such as Alzheimer's disease. Capsaicin, the primary pungent component in chili peppers, executes its anti-inflammatory properties as a TRPV1 agonist. Although the mechanism of TRPV1 channel activation and signal transduction by capsaicin has been extensively studied, the protein-protein interaction-based mechanisms by which TRPV1 modulates microglial inflammatory responses in the context of neurodegeneration remains unclear.</p><p><strong>Methods: </strong>We used a lipopolysaccharide-induced acute neuroinflammation model to examine the effects of TRPV1 activation and pharmacological blockade of TRPV1 channel gating on microglial inflammatory responses. Proximity labeling-based proteomics, bioluminescence resonance energy transfer, and NanoLuc Binary Technology were used to identify and characterize TRPV1-interacting proteins. Signal sequence receptor subunit 4 (SSR4) knockdown and forced interaction between TRPV1 and SSR4 were performed to assess the functional contribution of the TRPV1-SSR4 interaction. Structural modeling, BRET-based domain mapping, and colocalization analyses were further used to examine the molecular and subcellular features of SSR4 recruitment by TRPV1.</p><p><strong>Results: </strong>In the neuroinflammatory model, the TRPV1 agonist capsaicin attenuated pro-inflammatory cytokine production, neuronal apoptosis, microgliosis, and microglial soma enlargement in a TRPV1-dependent manner. Notably, pharmacological blockade of TRPV1 channel gating by capsazepine did not abolish the anti-inflammatory action of capsaicin, suggesting an alternative mechanism of action beyond the canonical ligand-gated Ca²⁺ influx. Screening of TRPV1 prey proteins and validation strategy identified SSR4 as a capsaicin-responsive, TRPV1-associated protein. SSR4 knockdown in microglia significantly diminished the suppression of inflammatory responses caused by TRPV1 activation. Conversely, forced interaction between TRPV1 and SSR4 partially mimicked the anti-inflammatory effects of TRPV1 activation. Further structural and cellular analyses suggested that the transmembrane region of TRPV1 supports SSR4 recruitment.</p><p><strong>Conclusions: </strong>Our findings suggest that capsaicin suppresses microglial inflammation mediated by the TRPV1-SSR4 interaction, providing new insights into the chemical biology basis of TRPV1 interoceptive signaling and potential applications of natural TRPV1 agonists for modifying therapy of neuroinflammation-associated neurodegeneration.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"15 1","pages":""},"PeriodicalIF":19.1,"publicationDate":"2026-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149228520","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":"Exercise promotes lipophagy and mitigates cognitive impairment in Alzheimer's disease through downregulating microglial TMEM9.","authors":"Liying Zhang, Shiyin Li, Xiaomeng Ma, Shimei Cheng, Ziying Ye, Shuhua Liu, Luping Qin, Huimin Dong, Yifeng Feng, Mingyue Li, Jinghui Xu, Lei Cai, Xiquan Hu, Xiaofei He","doi":"10.1186/s40035-026-00583-z","DOIUrl":"10.1186/s40035-026-00583-z","url":null,"abstract":"<p><strong>Background: </strong>Autophagy-lysosomal dysfunction contributes to lipid droplet (LD) accumulation, which drives pathological progression in Alzheimer's disease (AD). Exercise is reported to restore autophagy-lysosomal function and attenuate cognitive impairment in AD, but its regulation of LD deposition remains unknown.</p><p><strong>Methods: </strong>5×FAD transgenic mice underwent a three-month exercise intervention. Cognitive and emotional behaviors were assessed using the Morris water maze, novel object recognition, and open field test. LD deposition was evaluated by oil red O and BODIPY staining. Proteomic sequencing was performed to identify proteins affected by exercise. Pathological changes were examined by immunofluorescence, western blotting, and transmission electron microscopy. Intracerebroventricular injection of AAV was used to overexpress or knock down microglial TMEM9 to investigate the mechanisms by which physical exercise affects behavior and pathology in AD. In vitro, BV2 cells were cultured and incubated with oligomeric amyloid-β (oAβ), with or without oleic acid to induce LD formation. Chloroquine and rapamycin, which regulate autophagy-lysosomal function, were used to examine the effects of LDs on mitochondrial integrity under glucose deprivation conditions. Lentiviral or plasmid transfection was used to explore the key role of TMEM9 in regulating lipophagy, and the interaction between TMEM9 and ATP6AP1 was detected by co-immunoprecipitation. Clinically, plasma TMEM9 and ATP6AP1 levels in AD patients were measured by ELISA, and receiver operating characteristic (ROC) analysis was performed to evaluate diagnostic performance.</p><p><strong>Results: </strong>Exercise mitigated cerebral LD deposition through enhanced lipophagy, preserving mitochondrial integrity and attenuating cognitive decline. Mechanistically, exercise suppressed microglial TMEM9 expression, restoring LD degradation. Tmem9 downregulation facilitated LKB1 lysosomal translocation, activating AMPK signaling. In vitro, oleic acid-induced LDs preserved mitochondrial membrane potential and increased ATP production in BV2 microglia under glucose deprivation and oAβ exposure. Tmem9 overexpression exacerbated lipophagy impairment and mitochondrial dysfunction, whereas Tmem9 knockdown enhanced lipophagy and cytoprotection. Aβ clearance was negatively regulated by TMEM9. Clinically, AD patients exhibited characteristic Aβ deposition and glucose hypometabolism, with plasma TMEM9 levels strongly correlating with p-tau217 progression. Plasma TMEM9 and the TMEM9/ATP6AP1 ratio emerged as potential AD diagnostic biomarkers (AUC=0.791 and 0.853, respectively).</p><p><strong>Conclusion: </strong>These findings establish exercise-induced TMEM9 inhibition as a novel therapeutic strategy targeting lipidostasis to combat AD progression.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"15 1","pages":""},"PeriodicalIF":19.1,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13679003/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149224909","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ProSAAS overexpression arrests progression of motor deficits in a rat alpha-synuclein model of Parkinson's disease.","authors":"Zhan Shu, Hoa A Lam, Elizabeth J Videlock, Iris Lindberg, Nigel T Maidment","doi":"10.1186/s40035-026-00593-x","DOIUrl":"10.1186/s40035-026-00593-x","url":null,"abstract":"","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"15 1","pages":""},"PeriodicalIF":19.1,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13673805/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149208021","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Levetiracetam restores GABAergic function and network homeostasis following Vps35 deficiency in excitatory neurons.","authors":"Zhi-Peng Liu, Daehoon Lee, Zhibing Tan, Anika Wu, Lin Mei, Wen-Cheng Xiong","doi":"10.1186/s40035-026-00585-x","DOIUrl":"10.1186/s40035-026-00585-x","url":null,"abstract":"<p><strong>Background: </strong>Alzheimer's disease (AD) and related dementias (ADRDs) remain incurable, partly due to their complex and poorly understood pathogenic mechanisms. Loss of vacuolar protein sorting-associated protein 35 (VPS35), a core component of the retromer complex, has been implicated in AD and ADRDs. While Vps35 deficiency is known to increase amyloidogenesis by regulating its cargo proteins, such as APP and BACE1, the precise mechanism by which VPS35 dysfunction leads to cognitive impairment remains elusive. While neuronal VPS35 regulates trafficking and functions of multiple synaptic membrane proteins, such as postsynaptic glutamatergic and GABAnergic receptors and pre-synaptic vesicle protein SV2A, and Levetiracetam (LEV), an antiepileptic drug that improves cognition, interacts with the SV2A, exactly how LEV enhances cognition is still a matter of debate.</p><p><strong>Methods: </strong>Given the abundant expression of VPS35 in pyramidal excitatory neurons, we generated a conditional knockout mouse model with Vps35 deletion from postnatal glutamatergic excitatory neurons (Vps35^CaMKIIα) and characterized its phenotypes using a combination of behavioral assessments, and electrophysiological, biochemical, and immunohiotological analyses in the hippocampal CA1 region. A targeted pharmacological screen was conducted to evaluate the therapeutic potential of LEV.</p><p><strong>Results: </strong>Vps35 deletion did not disrupt the gross brain development but led to progressive cognitive decline beginning at three months of age. Electrophysiological analyses revealed earlier-onset hippocampal CA1 hyperexcitability, marked by depolarized resting membrane potentials and reduced Kir_2.1 expression. However, restoring Kir_2.1 to suppress hyperexcitability failed to rescue cognitive deficits. Instead, cognitive impairment was associated with weakened GABAergic transmission and disruption of the excitatory/inhibitory balance in the Schaffer collateral-CA1 circuit. Notably, LEV treatment diminished these deficits in mutant mice. Intriguingly, LEV increased the levels of retromer component, VPS26A, and multiple pre- and postsynaptic GABAergic proteins, in addition to SV2A, all of which were reduced in Vps35-deficient CA1 neurons.</p><p><strong>Conclusions: </strong>These findings identify VPS35 in excitatory neurons as a critical factor for inhibitory synapse maintenance and network homeostasis. This study also highlights LEV as a potential therapeutic strategy for ADRDs through the preservation of GABAergic synapses.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"15 1","pages":""},"PeriodicalIF":19.1,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13662985/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149184548","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The glymphatic-lymphatic axis: known pathways, open questions, and emerging roles in neurodegeneration.","authors":"Yumeng La, Jin Yuan, Jun Chen, Kejia Lv, Xiaoxi Wang, Qiqi Gao, Yujue Wang, Chen Wang, Bin Xu, Ying Yang, Jing Zhang","doi":"10.1186/s40035-026-00588-8","DOIUrl":"10.1186/s40035-026-00588-8","url":null,"abstract":"<p><p>The discovery of the glymphatic system and meningeal lymphatic vessels has transformed our understanding of brain fluid homeostasis and central-peripheral communication, highlighting the critical role of cerebrospinal fluid in brain clearance. While substantial progress has been made in defining the structural components and physiological regulators of brain clearance, major uncertainties remain regarding (1) how these systems interact as an integrated physiological network, (2) how they fail in disease, and (3) whether they can be therapeutically manipulated. In this review, we first summarize the anatomical and physiological organization of the glymphatic-lymphatic axis, with particular emphasis on its regulatory mechanisms in light of rapid advances in this field. We then discuss how the glymphatic-lymphatic axis functionally integrates with peripheral immune and metabolic systems and describe how impairment of these clearance pathways is associated with the accumulation of pathological proteins, neuroinflammation, and vascular dysfunction and may contribute to the progression of neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. Finally, we discuss emerging therapeutic strategies and biomarkers targeting the glymphatic-lymphatic axis. By redefining the central-peripheral crosstalk, the glymphatic-lymphatic axis provides a unifying framework for understanding brain clearance, neurodegeneration, and future therapeutic interventions.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"15 1","pages":""},"PeriodicalIF":19.1,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13651233/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149147911","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fyn kinase: a key mechanistic regulator and therapeutic target in tauopathy and neurodegenerative diseases.","authors":"Haiwen Wang, Xing Fan, Jianchao Ping, Qian Shao, Cai Wang, Hao Wang, Qiuhong Ji, Min Su, Wei Qian","doi":"10.1186/s40035-026-00590-0","DOIUrl":"https://doi.org/10.1186/s40035-026-00590-0","url":null,"abstract":"<p><p>Synaptic dysfunction and intracellular accumulation of pathological tau are convergent hallmarks of Alzheimer's disease (AD) and related tauopathies, yet the molecular mechanisms coupling these events to widespread neurodegeneration remain incompletely understood. The Src family kinase Fyn has emerged as a critical signaling hub that integrates upstream pathogenic triggers, such as amyloid-β (Aβ), with downstream neurotoxic cascades. Here, we review the multifaceted roles of Fyn in orchestrating synaptic failure, highlighting how Fyn recruitment by mislocalized tau promotes N-methyl-D-aspartate receptor hyperactivation and calcium dysregulation. We examine the biophysical basis of Fyn-tau interactions, particularly the role of liquid-liquid phase separation in stabilizing toxic signaling complexes. We also discuss how aberrant Fyn signaling in microglia and astrocytes amplifies neuroinflammation. Finally, we evaluate the potential of Fyn as a therapeutic target, emphasizing the necessity of strategies that selectively uncouple pathological signaling from physiological functions to effectively halt disease progression.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"15 1","pages":""},"PeriodicalIF":19.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13629038/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149115280","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microglia-derived extracellular vesicle content as a biomarker for early detection of Alzheimer's disease.","authors":"Amber L Woudstra, Linda Holtman, Erwin A van Vliet","doi":"10.1186/s40035-026-00587-9","DOIUrl":"https://doi.org/10.1186/s40035-026-00587-9","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-beta aggregation, tau pathology, synaptic dysfunction, and neuronal loss. While current biomarker frameworks such as the A/T/N classification have advanced diagnosis, they predominantly reflect relatively late stages of disease, limiting opportunities for early intervention. This underscores the urgent need for biomarkers that are not only accessible and sensitive but also specific to the earliest pathogenic mechanisms of AD. Recent work has underscored the pivotal role of disease-associated microglia (DAM) in the onset and progression of AD. DAM exhibit dual roles: they promote protection by phagocytosing amyloid and debris, metabolizing lipids, and remodelling synapses, yet can also drive pathology through excessive cytokine release, chronic inflammatory signalling, and impaired aggregate clearance. DAM release extracellular vesicles (EVs) that encapsulate proteins, nucleic acids, and lipids, reflective of their state. These vesicles reflect microglial (dys)function and can be detected in cerebrospinal fluid and blood, offering a minimally invasive means to monitor early AD pathology. In this review, we examine the emerging evidence that the content of microglia-derived EVs may fulfil the criteria of ideal biomarkers with a focus on the detectability, sensitivity, specificity, and feasibility for longitudinal monitoring. We discuss their potential to overcome limitations of current fluid and imaging biomarkers by offering more stable cargo protection, cell-type specificity, and accessibility in peripheral fluids. Furthermore, we highlight the opportunities and challenges in isolating microglia-derived EVs, identifying reliable surface and cargo markers, and standardizing methodologies for reproducibility across studies. By integrating insights from microglial biology with EV research, we provide evidence for microglia-derived EV content as biomarkers for early detection of AD and propose a roadmap toward DAM-specific EV signatures that could transform early AD diagnosis and disease monitoring. Such advances hold promise not only for AD but also for broader applications in neurodegenerative and neuroinflammatory disorders.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"15 1","pages":""},"PeriodicalIF":19.1,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13625476/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149115274","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Large-scale genetic profiling of hereditary ataxias in China: implications for a stepwise molecular diagnostic strategy.","authors":"Jin-Yang Yu, Yi-Min Sun, Yi Dong, Jian-Jun Wu, Chen-Hao Zhu, Yi-Chu Du, Yi-Xin Zhang, Yue Zhang, Sheng-Mei Zou, Yin Ma, Hai-Lin Dong, Zhi-Ying Wu","doi":"10.1186/s40035-026-00584-y","DOIUrl":"10.1186/s40035-026-00584-y","url":null,"abstract":"<p><strong>Background: </strong>Hereditary ataxias are clinically and genetically heterogeneous, which complicates clinical management, genetic counseling, and scientific research. Efficient molecular diagnosis is essential but requires molecular epidemiological considerations due to the variable genetic landscapes across regions and populations. In China, despite the established predominance of spinocerebellar ataxia type 3 (SCA3), comprehensive data on the genetic landscape of hereditary ataxias are limited and increasingly outdated, leaving insufficient evidence to support an epidemiology-informed molecular diagnostic strategy and its clinical implementation as a diagnostic algorithm.</p><p><strong>Methods: </strong>We retrospectively established a large, real-world, comprehensive cohort of hereditary ataxias (the HARMONY cohort) recruited from two medical centers in the Yangtze River Delta region of China (2008-2024) for genetic profiling. Molecular diagnoses were categorized into four classifications ('Definitive', 'Probable', 'Unclear', 'Undiagnosed') by integrating previously identified causative variants with results from systematic genetic testing in etiologically undetermined probands, and the associated variants were mapped onto genetic landscapes.</p><p><strong>Results: </strong>A total of 2096 probands were included in the HARMONY cohort, achieving a molecular diagnostic yield of 84.9%, with 1715 (81.8%) 'Definitive' and 65 (3.1%) 'Probable' positive diagnoses, alongside 87 (4.2%) 'Unclear' and 229 (10.9%) 'Undiagnosed' cases. While the genetic landscape was dominated by variants underlying SCA3 (1249; 59.6%), with SCA2 (150; 7.2%), SCA1 (139; 6.6%), SCA6 (51; 2.4%), putative SCA36 (36; 1.7%), and SCA12 (35; 1.7%) constituting the major subtypes, the genetic profiling revealed a long tail of rare genotypes. Onset age distributions were characterized for genotypes with ≥ 5 probands. No probands were found to carry expansions in ZFHX3, BEAN1, DAB1, THAP11, or FXN.</p><p><strong>Conclusions: </strong>Genetic profiling of the HARMONY cohort revealed a skewed genetic landscape dominated by a few common repeat-expansion subtypes, alongside a markedly heterogeneous long tail of rare etiologies. The holistic profile supports a stepwise molecular diagnostic strategy, under which we propose a YRD (Yangtze River Delta)-oriented candidate diagnostic algorithm. This study provides an evidence base for early molecular diagnosis, prioritization of therapeutic development, and adaptive design of diagnostic tools for hereditary ataxias.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"15 1","pages":""},"PeriodicalIF":19.1,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13621623/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149075869","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"What can we learn on ALS pathophysiology from iPSC-derived motor neurons harbouring TARBDP mutations: a systematic review.","authors":"Elena Pasho, Alberto Catanese, Edor Kabashi, Sorana Ciura","doi":"10.1186/s40035-026-00580-2","DOIUrl":"10.1186/s40035-026-00580-2","url":null,"abstract":"<p><p>The degenerating motor neurons of amyotrophic lateral sclerosis (ALS) patients are characterized by the accumulation of cytoplasmic aggregates, specifically enriched in ubiquitinated TDP-43. Expressed mainly in the nucleus and partially in the cytoplasm to execute its role in RNA metabolism, the exact mechanisms that bring TDP-43 to aggregate in disease have yet to be described. Unfolding these processes could bring us closer to effective drug development that is drastically lacking in the ALS research field. Induced pluripotent stem cells (iPSCs) offer a promising platform for studying ALS pathogenesis directly in the relevant human genetic backgrounds of ALS patients. Since 2012, more than 30 published studies have investigated altered cellular and subcellular features in iPSC-derived motor neurons from ALS patients harbouring mutations in the TARDBP gene (encoding for TDP-43 protein). However, there are discrepancies in the obtained results, which call into question the relevance of this model for ALS disease modelling and its use for drug development efforts. Thus, there is a need in the field for a clear and detailed layout and summary of all the published data on ALS modelling using TARDBP mutant iPSC-derived motor neurons. In this systematic review, we analyse all phenotypic assessments that have been done on iPSC-derived motor neurons derived from TARDBP ALS patients on the morphology, functionality and the viability of these cells. We also analyse if this model recapitulates ALS pathology in vitro by comparing studies that looked at TDP-43 and neurofilament aggregation, as well as stress granule dynamics. Importantly, we compare the technical details of all the discussed studies, such as differentiation protocol, age and purity of the used motor neurons and quantification method, in order to discuss how all of these parameters affect the observed phenotypes. Lastly, we also expand our review to all other different cell types that have been differentiated from TARDBP iPSCs, highlighting non-cell autonomous mechanisms of TDP-43-ALS pathophysiology. By integrating findings across studies, this review identifies commonalities and discrepancies, discusses methodological advancements and limitations, and highlights potential therapeutic targets revealed through TARDBP iPSC-derived models.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"15 1","pages":""},"PeriodicalIF":19.1,"publicationDate":"2026-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13589874/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149012770","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Species-dependent activities of the PINK1-parkin axis.","authors":"Wei Huang, Kecheng Chen, Jiayi Wen, Tong Zhang, Shihua Li, Xiao-Jiang Li, Weili Yang","doi":"10.1186/s40035-026-00586-w","DOIUrl":"10.1186/s40035-026-00586-w","url":null,"abstract":"<p><p>In vitro studies have established that PTEN-induced putative kinase 1 (PINK1) and parkin are central regulators of mitophagy, and loss-of-function mutations in either gene can cause early-onset Parkinson's disease (PD). Although various animal models, including mice and pigs with PINK1 or PRKN knockout, have largely failed to recapitulate the neurodegeneration seen in PD patients, effective knockdown of PINK1 or PRKN in non-human primates, when achieving substantial protein depletion, does induce dopaminergic neuron loss in the substantia nigra and α‑synuclein pathology, suggesting that both the degree of protein loss and the species-dependent PINK1-parkin axis activity contribute to PD pathogenesis. This review compares pathological and behavioral outcomes of PINK1- and parkin-deficient animal models across species, illustrates diverse functions of the PINK1-parkin axis beyond mitophagy, discusses mechanisms underlying the species-dependent differences, and highlights the therapeutic potential of targeting this pathway. The review also underscores the necessity of considering species-specific mechanisms when investigating the PINK1/parkin pathway.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"15 1","pages":""},"PeriodicalIF":19.1,"publicationDate":"2026-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13587387/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148991539","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}