Translational Neurodegeneration最新文献

{"title":"Targeted delivery of BACE1 siRNA for synergistic treatment of Alzheimer's disease.","authors":"Zhaohan Li, Jun Yang, Jianan Li, Shuxuan Zhao, Shaoping Jiang, Weimin Liu, Xinjian Li, Simeng Zhang, Haiyan Du, Junjun Ni, Yuanyu Huang, Hong Qing, Shaobo Ruan","doi":"10.1186/s40035-025-00503-7","DOIUrl":"10.1186/s40035-025-00503-7","url":null,"abstract":"<p><strong>Background: </strong>The deposition of toxic aggregated amyloid-β (Aβ), resulting from continuous cleavage of amyloid precursor protein (APP) by β-site APP cleaving enzyme 1 (BACE1) and γ-secretase, is a key pathogenic event in Alzheimer's disease (AD). Small interfering RNAs (siRNA) have shown great potential for disease treatment by specifically silencing target genes. However, the poor brain delivery efficiency of siRNAs limits their therapeutic efficacy against AD.</p><p><strong>Methods: </strong>We designed a simplified and effective BACE1 siRNA (siBACE1) delivery system, namely, dendritic polyamidoamine modified with the neurotropic virus-derived peptide RVG29 and polyethylene glycol (PPR@siBACE1).</p><p><strong>Results: </strong>PPR@siBACE1 crossed the blood-brain barrier efficiently and entered brain parenchyma in large amount, with subsequent neurotropism and potential microglia-targeting ability. Both in vitro and in vivo studies validated the effective brain delivery of siBACE1 and strong BACE1 silencing efficiency. Treatment of AD mice with PPR@siBACE1 inhibited the production of Aβ, potentiated Aβ phagocytosis by microglia, improved the memory deficits and reduced neuroinflammatory response in AD mice.</p><p><strong>Conclusions: </strong>This study provides a reliable delivery platform for gene therapies for AD.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"14 1","pages":"41"},"PeriodicalIF":15.2,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12351871/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144856434","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":"Role of extracellular vesicle-carried ncRNAs in the interactive 'dialogue' within the brain and beyond: emerging theranostic epigenetic modifiers in brain-derived nanoplatforms.","authors":"Nima Sanadgol, Pegah Mousavi, Fatemeh Sadri, Clara Voelz, Miriam Scheld, Roghayeh Khalseh, Javad Amini, Elham Karimi, Amid Rahi, Mohammad-Reza Sepand, Cordian Beyer, Markus Kipp","doi":"10.1186/s40035-025-00502-8","DOIUrl":"10.1186/s40035-025-00502-8","url":null,"abstract":"<p><p>Proper brain function and overall health critically rely on the bidirectional communications among cells in the central nervous system and between the brain and other organs. These interactions are widely acknowledged to be facilitated by various bioactive molecules present in the extracellular space and biological fluids. Extracellular vesicles (EVs) are an important source of the human neurosecretome and have emerged as a novel mechanism for intercellular communication. They act as mediators, transferring active biomolecules between cells. The fine-tuning of intracellular trafficking processes is crucial for generating EVs, which can significantly vary in composition and content, ultimately influencing their fate and function. Increasing interest in the role of EVs in the nervous system homeostasis has spurred greater efforts to gain a deeper understanding of their biology. This review aims to provide a comprehensive comparison of brain-derived small EVs based on their epigenetic cargo, highlighting the importance of EV-encapsulated non-coding RNAs (ncRNAs) in the intercellular communication in the brain. We comprehensively summarize experimentally confirmed ncRNAs within small EVs derived from neurons, astrocytes, microglia, and oligodendrocytes across various neuropathological conditions. Finally, through in-silico analysis, we present potential targets (mRNAs and miRNAs), hub genes, and cellular pathways for these ncRNAs, representing their probable effects after delivery to recipient cells. In summary, we provide a detailed and integrated view of the epigenetic landscape of brain-derived small EVs, emphasizing the importance of ncRNAs in brain intercellular communication and pathology, while also offering prognostic insights for future research directions.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"14 1","pages":"40"},"PeriodicalIF":15.2,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12323186/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144790054","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":"Axonal tau reduction ameliorates tau and amyloid pathology in a mouse model of Alzheimer's disease.","authors":"Abdolhossein Zare, Saeede Salehi, Jakob M Bader, Anna-Lena Wiessler, Manuela Prokesch, Vincent Albrecht, Carmen Villmann, Matthias Mann, Michael Briese, Michael Sendtner","doi":"10.1186/s40035-025-00499-0","DOIUrl":"10.1186/s40035-025-00499-0","url":null,"abstract":"<p><strong>Background: </strong>Pathological deposition of hyperphosphorylated tau in the brain closely correlates with the course of Alzheimer's disease (AD). Tau pathology occurs in axons of affected neurons and tau removal from axons might thus be an early intervention strategy.</p><p><strong>Methods: </strong>We investigated the role of the RNA-binding protein hnRNP R in axonal localization and local translation of Mapt mRNA in neurons cultured from hnRNP R knockout mice. hnRNP R knockout mice were crossed with 5×FAD mice, an AD mouse model, and the effects of hnRNP R loss on the deposition of phospho-tau and amyloid-β plaques were evaluated. We designed antisense oligonucleotides (MAPT-ASOs) to block the binding of hnRNP R to Mapt mRNA. Cultured mouse and human neurons were treated with MAPT-ASOs and axonal Mapt mRNA and tau protein levels were quantified. MAPT-ASO was injected intracerebroventricularly into 5×FAD mice followed by quantification of phospho-tau aggregates and amyloid-β plaques in their brains. Protein changes in brains of 5×FAD mice treated with the MAPT-ASO were measured by mass spectrometry.</p><p><strong>Results: </strong>Mapt mRNA and tau protein were reduced in axons but not cell bodies of primary neurons cultured from hnRNP R knockout mice. Brains of 5×FAD mice deficient for hnRNP R contained less phospho-tau aggregates and amyloid-β plaques in the cortex and hippocampus. Treatment of neurons with MAPT-ASOs to block hnRNP R binding to Mapt similarly reduced axonal tau levels. Intracerebroventricular injection of a MAPT-ASO reduced the phospho-tau and plaque load and prevented neurodegeneration in the brains of 5×FAD mice, accompanied by rescue of proteome alterations.</p><p><strong>Conclusion: </strong>Lowering of tau selectively in axons thus represents an innovative therapeutic perspective for treatment of AD and other tauopathies.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"14 1","pages":"39"},"PeriodicalIF":15.2,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12306013/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144745160","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":"Psychoactive substances: novel molecular insights and therapeutic potential for Alzheimer's disease.","authors":"Chonglei Fu, Xuehui Li, Xiaoxing Liu, Yongbo Zheng, Xiangxian Ma, Bo Zhang, Si Chen, Lingming Hu, Sizhen Su, Xiaokun Wang, Jie Sun, Qingqing Yin, Yumei Wang, Xiaolong Fu, Yanping Bao, Yanxue Xue, Tao Xin, Lin Lu, Guichang Zou","doi":"10.1186/s40035-025-00498-1","DOIUrl":"10.1186/s40035-025-00498-1","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is a major neurodegenerative disorder that causes severe cognitive decline and poses a significant burden on global health systems. Despite extensive research, effective treatments to stop neurodegeneration or promote neuronal regeneration in AD remain elusive. Psychoactive substances as modulators of neurophysiological functions, have received increased attention in research. The main psychoactive agents, such as central nervous system depressants and stimulants, cannabinoids, psychedelics, opioids and ketamine, are being explored for their abilities to enhance learning and cognitive performance and potential neurorestorative functions. In this paper, we review the molecular mechanisms and therapeutic potential of psychoactive substances in AD, in the aim to guide future research directions.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"14 1","pages":"38"},"PeriodicalIF":15.2,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12291523/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144718665","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":"Long-term exercise enhances meningeal lymphatic vessel plasticity and drainage in a mouse model of Alzheimer's disease.","authors":"Yan Chen, Jiachen Cai, Yuzhu She, Xiaoxin He, Hu Feng, Xuewei Li, Yiran Wei, Yi Fan, Wen-E Zhao, Mengmei Yin, Linjuan Yuan, Yuxi Jin, Fengfei Ding, Chengyu Sheng, Junying Gao, Qian Li, Ming Xiao","doi":"10.1186/s40035-025-00497-2","DOIUrl":"10.1186/s40035-025-00497-2","url":null,"abstract":"<p><strong>Background: </strong>Meningeal lymphatic drainage is crucial for the clearance of amyloid β (Aβ), supporting the maintenance of brain homeostasis. This makes it a promising therapeutic target for Alzheimer's disease (AD). Long-term exercise can reduce the risk of AD; however, the underlying mechanism is not fully understood. In this study, we investigated whether exercise alleviates AD-related pathological changes by improving meningeal lymphatic drainage and its potential mechanisms.</p><p><strong>Methods: </strong>The morphological and functional features of meningeal lymphatic vessels, as well as Aβ and reactive gliosis in the brain, were compared between 6.5-month-old 5 × FAD mice with or without 1 month of treadmill exercise. RNA sequencing, protein interactions analysis, gene knockdown mediated by adeno-associated virus, and lymphatic endothelial cell culture were conducted to investigate the mechanism underlying exercise-induced meningeal lymphatic vessel plasticity in 5 × FAD mice.</p><p><strong>Results: </strong>The structural integrity of meningeal lymphatic vessels was compromised in 5 × FAD mice, compared with the wild-type mice. Treadmill exercise increased the diameter and the drainage capacity of the meningeal lymphatic vessels, reduced Aβ deposition, reactive gliosis and astrocyte senescence in the hippocampus and frontal cortex, and improved cognitive function of 5 × FAD mice. Mechanistically, thrombospondin-1 (TSP-1) exacerbated the inhibitory effect of Aβ on lymphatic vessel formation and plasticity through interactions with CD36 and CD47, respectively. Exercise decreased the expression of TSP-1 in reactive astrocytes of AD mice by downregulating eleven-nineteen lysine-rich leukemia-associated factor 2 (EAF2), a protein that facilitates the transcription of the TSP-1-encoding gene Thbs-1 by binding p53. Ultimately, we found that hippocampal astrocyte-specific knockdown of Thbs-1 or Eaf2 enhanced meningeal lymphatic drainage and alleviated AD-like pathology in the hippocampus of 5 × FAD mice.</p><p><strong>Conclusions: </strong>Long-term exercise protects against AD by enhancing the plasticity and drainage of meningeal lymphatic vessels through downregulation of the EAF2-p53-TSP-1 pathway associated with reactive astrocytes.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"14 1","pages":"37"},"PeriodicalIF":15.2,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12291319/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144718664","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":"Glutathione oxidation in cerebrospinal fluid as a biomarker of oxidative stress in amyotrophic lateral sclerosis.","authors":"Trong Khoa Pham, Nick Verber, Martin R Turner, Andrea Malaspina, Mark Oliver Collins, Richard J Mead, Pamela J Shaw","doi":"10.1186/s40035-025-00496-3","DOIUrl":"10.1186/s40035-025-00496-3","url":null,"abstract":"","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"14 1","pages":"36"},"PeriodicalIF":10.8,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12232736/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144584963","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":"Dorsal hyperintensity and iron deposition patterns in the substantia nigra of Parkinson's disease, idiopathic REM sleep behavior disorder, and Parkinson-plus syndromes at 7T MRI: a prospective diagnostic study.","authors":"Dongning Su, Zhijin Zhang, Zhe Zhang, Rui Yan, Wanlin Zhu, Ning Wei, Yue Suo, Xinyao Liu, Ying Jiang, Lingyan Ma, Huiqing Zhao, Zhan Wang, Xuemei Wang, Huizi Ma, Xin Liu, Chaodong Wang, Zhirong Wan, Fangfei Li, Yuan Li, Joyce S T Lam, Junhong Zhou, Ning Zhang, Tao Wu, Jing Jing, Tao Feng","doi":"10.1186/s40035-025-00495-4","DOIUrl":"10.1186/s40035-025-00495-4","url":null,"abstract":"<p><strong>Background: </strong>Dorsal nigral hyperintensity (DNH) abnormality associated with excessive iron deposition in the substantia nigra, is recognized as an imaging characteristic of Parkinson's disease (PD) and can be effectively visualized using 7T MRI. This study was aimed to develop and validate the optimal DNH assessment method as a biomarker for PD, idiopathic rapid eye movement sleep behavior disorder (iRBD), and Parkinson-plus syndromes, and to explore the nigral iron deposition patterns in these diseases.</p><p><strong>Methods: </strong>Three-dimensional gradient-echo T2*-weighted images were acquired by 7T MRI from a total of 402 patients and 100 healthy controls (HCs) in two independent cohorts (development and validation cohorts). Seven methods, including four dichotomous methods and three DNH rating scales, were used to assess DNH and evaluate their diagnostic performance. R2* mapping and principal component analysis were performed to assess nigral iron deposition patterns.</p><p><strong>Results: </strong>Bilateral DNH detection rates in the development cohort were 22.6% for early-stage PD, 3.7% for advanced PD, 93.5% for iRBD, 5.7% for MSA-parkinsonian type, 78.8% for MSA-cerebellar type, 11.8% for progressive supranuclear palsy (PSP), and 100% for HC, with similar rates in the validation cohort. A cut-off of 6 on the 6-point visibility scale demonstrated a 100% accuracy for diagnosing early-stage PD in both the development and the validation cohorts. This scale exhibited moderate differential diagnostic performance between early-stage PD and iRBD (area under the curve [AUC] = 0.940) or MSA-C (AUC = 0.892). Iron deposition was predominantly in the dorsal and posterior substantia nigra of PD and PSP, the intermediate and posterior substantia nigra of MSA-P, and the ventral substantia nigra of MSA-C.</p><p><strong>Conclusion: </strong>DNH may be preserved in approximately one-quarter of early-stage PD and most MSA-C cases. The 6-point visibility scale on 7T effectively distinguished PD from HC, iRBD, and MSA-C. The nigral iron deposition pattern in PD may help distinguish PD from MSA-P and MSA-C, although it overlaps with that of PSP.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"14 1","pages":"35"},"PeriodicalIF":10.8,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12231697/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144565328","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":"Immunization targeting diseased proteins in synucleinopathy and tauopathy: insights from clinical trials.","authors":"Xiaoni Zhan, Gehua Wen, Xu Wu, Jia-Yi Li","doi":"10.1186/s40035-025-00490-9","DOIUrl":"10.1186/s40035-025-00490-9","url":null,"abstract":"<p><p>Synucleinopathies and tauopathies are neurodegenerative disorders characterized by the pathological accumulation of α-synuclein (α-syn) and tau proteins, respectively. These disorders are traditionally managed with symptomatic treatments without addressing the underlying pathologies. Recent advancements in passive immunotherapies, notably the FDA approval of the amyloid-beta (Aβ)-targeting antibody lecanemab, have sparked new hope in directly targeting pathological proteins. However, unlike the extracellular Aβ pathology, immunotherapies aimed at α-syn and tau, which predominantly form intracellular inclusions, face substantial challenges. To date, the therapeutic efficacy of five α-syn and 14 tau antibodies has been assessed in patients with synucleinopathies and tauopathies. These immunizations have demonstrated promising preclinical outcomes in alleviating pathological and behavioral deficits, but have not yielded significant clinical improvements in symptoms or measurable biomarkers. Therefore, a clear understanding of potential causes for the discrepancies between preclinical successes and clinical outcomes is critical for the successful translation of immunotherapy in the future. In this review, we examine existing passive immunotherapeutic strategies targeting α-syn and tau, specifically in patients with Alzheimer's disease and Parkinson's disease. Lessons learned from initial trial failures are also discussed, including refinement of animal models, inclusion and stratification of participants, improvement of clinical evaluations, and development of biomarkers. Given the overlapping pathologies and clinical manifestations of synucleinopathies and tauopathies, we further explore the potential of combined therapies targeting co-pathologies, offering novel insights for future therapeutic development against these neurodegenerative disorders.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"14 1","pages":"33"},"PeriodicalIF":10.8,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12211364/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144529709","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":"Deficient AMPK-SENP1-Sirt3 signaling impairs mitochondrial complex I function in Parkinson's disease model.","authors":"Xiaoyu Sun, Jianyi Shen, Yimei Shu, Tianshi Wang, Lu He, Ruinan Shen, Yifan Zhou, Jinke Cheng, Suzhen Lin, Jianqing Ding","doi":"10.1186/s40035-025-00489-2","DOIUrl":"10.1186/s40035-025-00489-2","url":null,"abstract":"<p><strong>Background: </strong>Epidemiological studies have revealed increased Parkinson's disease (PD) risk among individuals exposed to pesticides like 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). MPTP is frequently used to induce PD-like symptoms in research models by disrupting mitochondrial complex I (CI) function and causing dopaminergic neuronal loss in the nigrostriatal region. However, the pathway(s) through which MPTP impairs mitochondrial CI function remain to be elucidated. In this study, we aim to identify the molecular mechanisms through which MPTP modulates CI function and define the specific subunits of mitochondrial CI affected by MPTP.</p><p><strong>Methods: </strong>Male mice encompassing either wild-type Sirt3 or Sirt3 K223R de-SUMOylation mutation, were intraperitoneally injected with either MPTP or saline. In vitro experiments were conducted using the SH-SY5Y cell line with or without the Sirt3 de-SUMOylation mutation. Movement performance, mitochondrial function, and protein acetylation were evaluated.</p><p><strong>Results: </strong>MPTP exposure, both in vitro and in vivo, disrupted the AMPK-SENP1-Sirt3 axis, leading to impairment of mitochondrial function. Specifically, MPTP suppressed activation of AMPK, impeding the entry of SENP1 into the mitochondria. The lack of mitochondrial SENP1 resulted in increased levels of SUMOylated Sirt3, which inhibited its deacetylase activity. This led to a significant increase in the acetylation of CI subunits NDUFS3 and NDUFA5, which resulted in reduced CI activity and inhibition of mitochondrial function, and eventually dopaminergic neuronal death. In this pathway, sustained deSUMOylation mutation of Sirt3 (K223R in mice, K288R in humans) mitigated the impact of MPTP on mitochondrial dysregulation, as well as dopaminergic neuronal death and behavioral deficits.</p><p><strong>Conclusion: </strong>The disordered AMPK-SENP1-Sirt3 pathway plays a crucial role in the MPTP-induced CI dysfunction and PD-like phenotype, which provide valuable insights into the mechanisms of PD pathogenesis.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"14 1","pages":"34"},"PeriodicalIF":10.8,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12211261/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144544985","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":"Abnormal α-synuclein binds to synaptotagmin 13, impairing extracellular vesicle release in synucleinopathies.","authors":"Yasuo Miki, Shuji Shimoyama, Makoto T Tanaka, Hanae Kushibiki, Asa Nakahara, Xiaopeng Wen, Masanori Hijioka, Tomoya Kon, Megha Murthy, Tomonori Furukawa, Conceição Bettencourt, Fumiaki Mori, Hiroki Mizukami, Shirushi Takahashi, Mari Tada, Yoshihisa Kitamura, Akiyoshi Kakita, Thomas T Warner, Koichi Wakabayashi","doi":"10.1186/s40035-025-00493-6","DOIUrl":"10.1186/s40035-025-00493-6","url":null,"abstract":"<p><strong>Background: </strong>Despite increasing in vitro research, direct evidence of how abnormal α-synuclein (α-Syn) dysregulates vesicular transport and synaptic function in the human brain is lacking.</p><p><strong>Methods: </strong>We performed a transcriptome analysis using brain tissues from a multiple system atrophy (MSA) mouse model, which develops human α-Syn-positive glial cytoplasmic inclusion-like structures and neuronal cytoplasmic inclusion-like structures after tamoxifen injection. We then performed histologic and biochemical analyses using brain samples from 71 human cases (Parkinson's disease, n = 10; dementia with Lewy bodies [DLB], n = 19; MSA, n = 15; control: n = 27), a human blood sample (control: n = 1), and cultured cells.</p><p><strong>Results: </strong>Based on the transcriptome of the MSA mouse model, we identified 10 vesicular transport proteins, including synaptotagmin 13 (SYT13), that might interact with α-Syn. Immunohistochemistry using human brain samples demonstrated that of the 10 vesicular transport proteins identified in the transcriptome analysis, only SYT13 was incorporated into both Lewy bodies and glial cytoplasmic inclusions. Proximity ligation assays revealed that SYT13 exhibited a higher degree of interactions with phosphorylated α-Syn than with endogenous α-Syn. Immunoprecipitation confirmed that SYT13 bound predominantly to phosphorylated α-Syn, SYT1, and the soluble N-ethylmaleimide-sensitive attachment protein receptor (SNARE) complexes. Filter trap assays revealed interactions between SYT13 and soluble toxic β-sheet-rich α-Syn oligomers. Furthermore, fraction analysis showed a significant increase of SYT13 protein levels at the synapses in DLB and MSA. Notably, a correlation was observed between the levels of SYT13 and aggregated α-Syn at the synapses. SYT13 was observed to regulate extracellular vesicle release in association with SYT1 and the SNARE complexes in SH-SY5Y cells. SYT13 overexpression in SH-SY5Y cells impaired extracellular vesicle release. Consistently, the numbers of extracellular vesicles were significantly reduced in the brain homogenates of DLB and MSA cases compared with those in controls.</p><p><strong>Conclusions: </strong>Abnormal α-Syn impairs extracellular vesicle release through interactions with SYT13 in synucleinopathies. Our findings provide insights into therapeutic strategies for alleviating dysregulations of vesicular transport and synaptic function in patients with synucleinopathies.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"14 1","pages":"32"},"PeriodicalIF":10.8,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12183919/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144476820","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}