Translational Neurodegeneration最新文献

{"title":"Targeting lysosomal pH restores mitochondrial quality control in GBA1-mutant Parkinson's disease.","authors":"Preethi Sheshadri, Maria Alicia Costa-Besada, Alessia Fisher, Szilvia Kiraly, Kritarth Singh, Ioanna Kourouzidou, Thomas S Blacker, Jialiu Zeng, Orian S Shirihai, Mark W Grinstaff, Michael R Duchen","doi":"10.1186/s40035-026-00559-z","DOIUrl":"10.1186/s40035-026-00559-z","url":null,"abstract":"<p><strong>Background: </strong>Heterozygous mutations in the glucocerebrosidase gene (GBA1), which encodes the lysosomal enzyme β-glucocerebrosidase (GCase), are a genetic risk factor for Parkinson's disease (PD). The pathophysiological consequences of GBA1 mutations on dopaminergic neuronal function, especially their impact on lysosomal function, mitophagy, and mitochondrial bioenergetics, remain unclear.</p><p><strong>Methods: </strong>Fibroblasts and dopaminergic neurons generated from induced pluripotent stem cells (iPSCs) derived from patients with GBA1-PD were used in the study. Live-cell imaging was performed to measure lysosomal acidification, protease activity, mitochondrial membrane potential, and mitophagy. Mitochondrial morphology and autophagic vesicles were examined using transmission electron microscopy. Oxygen consumption rate was measured by Seahorse assay. V-ATPase assembly was quantified using fluorescence lifetime imaging with Förster resonance energy transfer (FLIM-FRET), and pharmacological interventions included rapamycin and acidic nanoparticles.</p><p><strong>Results: </strong>GCase activity, lysosomal acidification, protease activity, mitophagy and mitochondrial bioenergetic function were all impaired in GBA1 mutant dopaminergic neurons. Mitochondria were fragmented, with reduced membrane potential and oxygen consumption. Mechanistic target of rapamycin complex 1 (MTORC1) was constitutively phosphorylated and FLIM-FRET measurements confirmed impairment of lysosomal V-ATPase assembly, which was reversed by rapamycin treatment. Rapamycin and lysosome-targeting acidic nanoparticles rescued lysosomal pH and restored mitophagy, mitochondrial membrane potential and mitochondrial oxidative phosphorylation complex level in the GBA1 mutant dopaminergic neurons.</p><p><strong>Conclusions: </strong>We revealed a novel mechanistic link between GBA1 mutations and mitochondrial dysfunction, as the disruption of V-ATPase assembly driven by MTORC1 activation impairs lysosomal acidification. This causes impairment of mitophagy, leading to mitochondrial dysfunction, undermining dopaminergic cell function and fate. Pharmacological intervention with rapamycin or acidic nanoparticles restores lysosomal pH and rescue mitochondrial function, representing a novel therapeutic approach for GBA1-PD .</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"15 1","pages":""},"PeriodicalIF":19.1,"publicationDate":"2026-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13277009/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148273080","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":"Persistent PirB cleavage drives Golgi-directed trafficking deficits underlying neurodegeneration.","authors":"Wu-Bo Han, Xian-Dong Liu, Chang-Fei Tang, Junke Zheng, Tian-Le Xu, Nan-Jie Xu, Suya Sun","doi":"10.1186/s40035-026-00553-5","DOIUrl":"10.1186/s40035-026-00553-5","url":null,"abstract":"<p><strong>Background: </strong>Extensive research evidence indicates that neuronal immune receptors play a critical role in Alzheimer's disease (AD). However, it remains unclear how these receptors convert extracellular signals into cellular pathological changes. Proteolytic cleavage of membrane receptors serves as an unconventional pathway for reprogramming cellular functions, and the cleaved fragments often play important roles within the cell. Whether immune receptors mediate their effects in AD through this cleavage-dependent signaling mechanism remains to be clarified.</p><p><strong>Methods: </strong>We performed proteomic screening of human cerebrospinal fluid to identify cleaved membrane proteins. Cleavage events were validated in postmortem AD brains, primary neurons, and APP/PS1 mice by immunoprecipitation, liquid chromatography-tandem mass spectrometry (LC-MS/MS), and immunofluorescence. Functional impacts were assessed through cathepsin D maturation assays, Retention Using Selective Hooks (RUSH) systems, live imaging of axonal transport, and behavioral tests (e.g., Barnes maze and fear conditioning). Therapeutic potential was evaluated by inhibiting the paired immunoglobulin-like receptor B (PirB) cleavage and overexpression of the GAT domain of Golgi-associated, gamma adaptin ear-containing, ARF binding protein 3 (GGA3).</p><p><strong>Results: </strong>This study identified a pathogenic proteolytic pathway in AD patients and mouse models, which cleaves PirB, a mouse ortholog of human leukocyte immunoglobulin-like receptor B2 (LILRB2), upon Aβ exposure, generating a C-terminal fragment (PirB-CTF) that accumulated in the Golgi apparatus via retrograde transport. PirB-CTF bound to the GAT domain of GGA3, disrupting Golgi transport, impairing lysosomal maturation, and compromising anterograde synaptic vesicle transport. Inhibiting PirB cleavage or overexpressing GGA3-GAT restored Golgi function, reduced Aβ plaque burden and tau phosphorylation, and rescued memory deficits.</p><p><strong>Conclusion: </strong>Our study revealed a non-canonical pathway in which proteolytic cleavage repurposes PirB into an intracellular disruptor of Golgi trafficking, directly coupling immune receptor activation to organelle dysfunction in AD. The PirB-CTF/GGA3 interface represents a promising therapeutic target for mitigating trafficking deficits and cognitive decline in neurodegenerative disorders.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"15 1","pages":""},"PeriodicalIF":19.1,"publicationDate":"2026-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13231542/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148151386","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":"From phenotype to biology: a multi-modal roadmap of biofluid, tissue, imaging, and digital biomarkers in Parkinson's disease.","authors":"Zhenwei Yu, Dongning Su, Siming Li, Shinuan Lin, Kang Ren, Tao Feng","doi":"10.1186/s40035-026-00558-0","DOIUrl":"10.1186/s40035-026-00558-0","url":null,"abstract":"<p><p>The definition of Parkinson's disease (PD) is undergoing a profound transformation from a \"clinical syndrome\" to a \"biological entity\", with development of two objective biological classification systems, the NSD-ISS (Neuronal Alpha-Synuclein Disease Integrated Staging System) and the SynNeurGe framework. Multimodal diagnostic tools further improve the detection of PD. This review synthesizes advances in three key domains of PD detection. First, fluid and tissue biomarkers, particularly using α-synuclein (αSyn) seed amplification assays, allow detection of synucleinopathy in cerebrospinal fluid, blood, saliva, and skin. This supports pathological diagnosis and differential classification. Extracellular vesicles provide cell-type-specific cargo profiles, while neurofilament light chain indicates neuroaxonal injury. Second, neuroimaging captures in vivo pathology. MRI identifies nigral degeneration (nigrosome-1 loss, iron accumulation, neuromelanin depletion), MRS reveals metabolic and neurotransmitter imbalances, and αSyn positron emission tomography tracers enable direct visualization of aggregation. Third, digital biomarkers derived from wearable devices, videos, and audios quantify real-world motor and non-motor symptoms, enabling continuous, ecological monitoring. Integration of these complementary biomarker streams is essential for biological definition and stratification of PD patients, and development of targeted therapies. Standardization of assays, multicenter validations, and clear guidance on who should be tested, when testing is appropriate, and how results should inform diagnosis, stratification, or monitoring are required for the translation of these methods into clinical practice in PD.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"15 1","pages":""},"PeriodicalIF":19.1,"publicationDate":"2026-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13217808/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148057204","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":"Ketogenic diet as a therapeutic strategy for neurodegenerative diseases: from mechanisms to translational challenges.","authors":"Ana Margarida Salgueiro, Marisa Ferreira-Marques, Rodrigo F N Ribeiro, Sara M Lopes, Dina Pereira, Daniela G Costa, Magda M Santana, Luís Pereira de Almeida, Cláudia Cavadas","doi":"10.1186/s40035-026-00557-1","DOIUrl":"10.1186/s40035-026-00557-1","url":null,"abstract":"<p><p>The ketogenic diet (KD) is increasingly recognized as a promising therapeutic strategy for neurodegenerative disorders because of its multifaceted impacts on key pathophysiological mechanisms. This review explores the molecular pathways through which KD may protect against neurodegeneration, including the use of ketone bodies as alternative energy substrates, reduction of oxidative stress and inflammation, modulation of autophagy and protein aggregation, and impact on the gut microbiome. The potential benefits of KD are explored across neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and multiple sclerosis, based on both preclinical and clinical evidence that supports its feasibility. However, challenges in long-term safety, patient adherence, and clinical practicality limit its widespread adoption. This review underscores the potential of KD for treating neurodegeneration on the basis of current scientific evidence while highlighting the need for further research to optimize its application and address existing gaps.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"15 1","pages":""},"PeriodicalIF":19.1,"publicationDate":"2026-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13200306/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148017530","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":"Mesenchymal stromal cells and neuroinflammation: a multimodal approach to neuroprotection and future therapeutic horizons.","authors":"Alexandro Angelo Bufi, Andrea Papait, Peter Ponsaerts, Antonietta Rosa Silini, Ornella Parolini","doi":"10.1186/s40035-026-00554-4","DOIUrl":"10.1186/s40035-026-00554-4","url":null,"abstract":"<p><p>As the global population ages, neurodegenerative and neuroinflammatory diseases are becoming a rapidly growing public health challenge, with available interventions remaining largely symptomatic and often only modestly affecting long-term disease progression. Therapies involving mesenchymal stromal cells (MSCs) have attracted substantial attention as a potential clinical therapeutic strategy across chronic central nervous system (CNS) disorders, due to their multifaceted ability to modulate immune response and confer neuroprotection. While initially explored for their multilineage differentiation potential, MSCs are now predominantly recognized for their paracrine functions, including secretion of soluble factors and extracellular vesicles. These acellular mediators induce diverse neuroprotective effects by attenuating neuroinflammation, stabilizing the blood-brain barrier, reprogramming glial and lymphocyte activity, and delivering regulatory microRNAs that modulate neuronal apoptosis and inflammatory gene networks. In this review, we summarize molecular evidence from in vitro and in vivo preclinical models, and early clinical investigations that demonstrate how tissue source and immunobiological plasticity shape the efficacy of MSCs. We further highlight emerging trends toward acellular MSC-derived therapies, offering a mechanistically versatile platform for therapeutic interventions for common neurodegenerative and neuroinflammatory disorders of the CNS, particularly Alzheimer's disease, Parkinson's disease and multiple sclerosis, a primary autoimmune demyelinating disorder.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"15 1","pages":""},"PeriodicalIF":19.1,"publicationDate":"2026-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13182032/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147964658","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":"Calbindin-D28k deficiency mediates tau-driven hippocampal hyperexcitement and cognitive impairment.","authors":"Yang Gao, Xiaoqing Tao, Yuying Wang, Yarong Wang, Huan Li, Yang Yu, Mengqi Tu, Yanchao Liu, Jie Zhou, Yuchen Li, Wei Wei, Xiaochuang Wang, Jie Zheng, Yao Zhang, Haibo Xu, Jian-Zhi Wang","doi":"10.1186/s40035-026-00547-3","DOIUrl":"10.1186/s40035-026-00547-3","url":null,"abstract":"<p><strong>Background: </strong>Medial temporal lobe hyperexcitation or seizures originating from the hippocampus are frequently observed in Alzheimer's disease (AD) patients, contributing to accelerated cognitive decline. As the hippocampus is an early vulnerable area of tau pathology, the mechanisms by which abnormal tau aggregation promotes temporal lobe epilepsy (TLE) remain poorly understood.</p><p><strong>Methods: </strong>We investigated the role of AD-like hippocampal tau aggregation in neuronal hyperexcitation using transgenic (Tg) tau-driven mice. Effects of tau aggregation on intracellular calcium dynamics were assessed by calcium imaging. Neuronal/network hyperexcitability and seizure susceptibility were evaluated through patch-clamp electrophysiology, ¹⁸F-FDG PET/CT, and optogenetic induction. A tetracycline-controlled (Tet-on) system in Tg hTau368 mice enabled spatiotemporal induction of tau pathology to investigate its interactions with calbindin-D28k (CB) and synaptic proteins. Adeno-associated virus (AAV)-mediated CB supplementation in hippocampal CA1 and dentate gyrus (DG) excitatory neurons was performed to correct hyperexcitability and cognitive deficits. Finally, the relationship between CB and disease progress was analyzed using an AD public database.</p><p><strong>Results: </strong>Tau accumulation in the hippocampal CA1/DG CaMKII-positive excitatory neurons reduced CB expression with disruption of calcium homeostasis. This dysregulation increased neuronal excitability, diminished synaptic protein levels, and increased seizure susceptibility and cognitive impairment. AAV-driven CB restoration in CA1/DG neurons attenuated both hyperexcitability and cognitive deficits. In the brains of AD patients, reduced CB expression was associated with cognitive deterioration and advanced disease stages.</p><p><strong>Conclusions: </strong>Tau aggregation drives calcium dysregulation and hippocampal neuronal hyperexcitation through reducing CB expression. These results establish a potential mechanistic link between tauopathy and TLE pathogenesis in AD, providing evidence for CB as a promising therapeutic target for mitigating seizure risk and related cognitive decline in AD.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"15 1","pages":""},"PeriodicalIF":19.1,"publicationDate":"2026-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13162517/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147933708","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 emerging role and therapeutic targeting of autophagy-lysosome pathway in the pathogenesis of Parkinson's disease.","authors":"Takahiro Shimizu, Sanem Isik, Nitika Kamath, Zhenyu Yue","doi":"10.1186/s40035-026-00555-3","DOIUrl":"10.1186/s40035-026-00555-3","url":null,"abstract":"<p><p>Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by dopaminergic neuron loss and the accumulation of misfolded α-synuclein, yet the underlying mechanisms remain incompletely understood. Over the past two decades, genetic discoveries have highlighted the convergence of multiple familial PD genes on the autophagy-lysosome pathway (ALP), a key cellular system responsible for the degradation and recycling of intracellular components. Recent studies have further revealed that components of the ALP not only mediate the clearance of α-synuclein aggregates but also, under certain pathological conditions, contribute to their propagation via lysosomal exocytosis or secretory autophagy. The precise functions of autophagy are highly context-dependent, with neuronal and glial cells exhibiting distinct ALP dynamics that shift with development, stress, and aging. In this review, we summarize current knowledge on the physiological regulation of autophagy in the brain and critically examine its involvement in PD pathogenesis, incorporating mechanistic insights from familial models and emerging evidence from sporadic PD. We also explore translational implications, focusing on efforts to identify ALP-related biomarkers in cerebrospinal fluid and urine, and on the therapeutic potential of modulating ALP activity. Although the causality between ALP dysfunction and PD remains elusive, mounting evidence supports its contribution to disease progression, particularly through impaired lysosomal homeostasis and disrupted intracellular trafficking. Future research should aim to define cell type-specific ALP alterations, clarify the bidirectional interactions between α-synuclein and autophagic machinery, and develop in vivo tools to monitor autophagy activity and secretory signatures. A deeper understanding of these processes will be crucial for refining PD models, discovering robust fluid biomarkers, and designing targeted therapies capable of modifying disease trajectory.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"15 1","pages":""},"PeriodicalIF":19.1,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13151188/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147843204","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":"A new dawn for Parkinson's disease: commentary on the emergence of stem cell-based therapies.","authors":"Rosalie Elvira, Wai Hon Chooi, Hongyan Wang, Eng King Tan, Zhi Dong Zhou","doi":"10.1186/s40035-026-00556-2","DOIUrl":"10.1186/s40035-026-00556-2","url":null,"abstract":"<p><p>The field of regenerative medicine for Parkinson's disease (PD) has reached a pivotal moment. After decades of preclinical research, recent first-in-human clinical trials demonstrated that cell replacement therapy using stem cell-derived dopaminergic neurons is not only feasible and safe but also shows promising signs of efficacy. Here we analyze three landmark 2025 studies, including the phase I/II trial of allogeneic induced pluripotent stem cell-derived dopaminergic progenitors, that mark a significant leap forward for PD therapy. We discuss principles underpinning the therapy, the historical context of fetal tissue transplants, findings from recent trials, and critical challenges. The convergence of robust cell manufacturing, precise stereotactic surgery, and advanced neuroimaging provides compelling evidence that stem cell-based therapies are potentially a viable treatment paradigm for PD.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"15 1","pages":""},"PeriodicalIF":19.1,"publicationDate":"2026-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13126771/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147782065","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":"N-terminally acetylated Met11-Tau: a new pathological truncated Tau species with functional relevance in Alzheimer's disease.","authors":"Sarah Guedjdal, Coline Leghay, Maxime Derisbourg, Sabiha Eddarkaoui, Simon Lecerf, Florian Vermon, Raphaelle Caillierez, Séverine Begard, Claire Regost, Charlotte Laloux, Paulo J da Costa, Kevin Carvalho, Giovanni Chiappetta, Yann Verdier, Valérie Buée-Scherrer, Vincent Deramecourt, Susanna Schraen, David Blum, Franck Martin, Luc Buée, Malika Hamdane","doi":"10.1186/s40035-026-00550-8","DOIUrl":"10.1186/s40035-026-00550-8","url":null,"abstract":"<p><strong>Background: </strong>Tauopathies are a group of neurodegenerative diseases, including Alzheimer's disease (AD), characterized by progressive accumulation of pathological Tau proteins. Among the diverse Tau species, truncated variants are emerging as key contributors, yet their identity remains elusive, particularly for the N-terminal truncated ones. The present study identifies and characterizes a novel N-terminally truncated and N-alpha-acetylated form of the Tau protein, named AcMet11-Tau.</p><p><strong>Methods: </strong>We identified AcMet11-Tau by further analyses of previous proteomic data (capillary liquid chromatography-tandem mass spectrometry). We developed a monoclonal antibody, termed 2H2D11, by hybridoma method. The specificity of 2H2D11 was validated by ELISA, Western blot and immunohistochemistry. Expression of AcMet11-Tau in transgenic mouse model of Tau pathology and postmortem brain tissues was analyzed by ELISA and/or immunohistochemistry. Overexpression of AcMet11-Tau in the mouse brain was achieved by stereotaxic injections of lentiviral vectors carrying the coding sequence in the hippocampus. To neutralize AcMet11-Tau, transgenic mice received repeated intraperitoneal immunizations with either 2H2D11 or control antibody. The effects on Tau pathology were assessed by immunohistochemistry, qPCR, and behavioral assays.</p><p><strong>Results: </strong>Using 2H2D11, the newly developed antibody specifically targeting the AcMet11-Tau variant, we demonstrated that this species accumulated early in degenerating neurons in both transgenic mouse models of AD-related Tau pathology and post-mortem brain tissues from AD patients. Importantly, in vivo functional experiments revealed that expression of this truncated Tau species exacerbated Tau pathology in the transgenic mice, whereas targeted immunotherapeutic with the specific 2H2D11 antibody significantly reduced pathological Tau accumulation and prevented associated memory impairments.</p><p><strong>Conclusion: </strong>These findings position this newly identified Tau variant as a marker of neurofibrillary degeneration and a Tau species that contributes to disease-associated pathological processes, supporting its potential as a therapeutic target in Tau-related disorders, notably AD.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"15 1","pages":""},"PeriodicalIF":19.1,"publicationDate":"2026-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13123110/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147782108","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 Drp1-CoQ10-Coa6-ETC axis represents a therapeutic potential for working memory impairment caused by neuronal mitochondrial dysfunction.","authors":"Jingjing Tie, Shujiao Li, Xin Huang, Keke Ren, Ziwei Ni, Xiaodong Li, Changlei Zhu, Hui Liu, Feifei Wu, Yanling Yang, Yayun Wang","doi":"10.1186/s40035-026-00552-6","DOIUrl":"10.1186/s40035-026-00552-6","url":null,"abstract":"<p><strong>Background: </strong>Coenzyme Q10 (CoQ10) is a key mitochondrial electron carrier and a widely used dietary supplement with potential neurological benefits. However, the mechanisms underlying its effect in ameliorating memory deficits caused by cerebellar injury are not fully understood. In this study, we investigated the effects of long-term CoQ10 supplementation on working memory and the underlying mechanisms.</p><p><strong>Methods: </strong>Network pharmacology analysis was used to identify genetic targets of CoQ10 in cerebellar injury-related cognitive impairment. Purkinje cell (PC)-specific Drp1-deficient mice (PC-Drp1^-/-) were generated to model mitochondrial dysfunction. Behavioral performance was evaluated using the eight-arm radial maze. Mitochondrial structure and respiratory chain complex levels were evaluated by morphological and biochemical assays. Molecular targets of CoQ10 were identified using integrated drug-target engagement approaches, and their functional relevance was tested by viral vector-mediated overexpression.</p><p><strong>Results: </strong>The PC-Drp1^-/- mice displayed progressive working memory impairment and decreased PC density, accompanied by disrupted mitochondrial morphology and reduced activities of electron transport chain complexes III-V. Long-term CoQ10 treatment significantly reduced working memory errors and preserved PC numbers in PC-Drp1^-/- mice. Target engagement analyses identified cytochrome c oxidase assembly factor 6 (Coa6) as a direct binding target of CoQ10. Viral vector-mediated overexpression of Coa6 in PCs partially recapitulated the CoQ10-associated improvements in respiratory chain complex levels and working memory, whereas Coa6 knockdown attenuated these benefits.</p><p><strong>Conclusions: </strong>CoQ10 directly interacts with Coa6 to enhance mitochondrial respiratory chain function and preserve PC integrity in the context of Drp1 deficiency. Our findings suggest a promising mechanistic pathway for CoQ10-based intervention in memory deficits associated with mitochondrial dysfunction.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"15 1","pages":""},"PeriodicalIF":19.1,"publicationDate":"2026-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13112672/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147782137","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}