Translational Neurodegeneration最新文献

{"title":"Aging-dependent YAP1 reduction contributes to AD pathology by upregulating the Nr4a1-AKT/GSK-3β axis.","authors":"Ling Lei, Yilei Cheng, Anqi Yin, Jian-Min Han, Gang Wu, Fumin Yang, Qi Wang, Jian-Zhi Wang, Rong Liu, Hong-Lian Li, Xiaochuan Wang","doi":"10.1186/s40035-025-00487-4","DOIUrl":"10.1186/s40035-025-00487-4","url":null,"abstract":"<p><strong>Background: </strong>Aging is the greatest risk factor for late-onset Alzheimer's disease (LOAD), which accounts for > 95% of all Alzheimer's disease (AD) cases. Yes-associated protein 1 (YAP1), an aging-dependent protein, is a key element in the classical Hippo-YAP1 pathway mediated by a kinase cascade. Research showed that YAP1 was markedly reduced in the brains of individuals with AD. However, the mechanisms underlying the susceptibility of the Hippo-YAP1 signaling pathway in the context of LOAD remain unclear.</p><p><strong>Methods: </strong>AAV9-YAP1-RNAi was injected into the hippocampi of C57BL/6J mice to establish a YAP1 knockdown model. Overexpression of full-length YAP1 was achieved by injecting AAV9-YAP1 into the hippocampi of SAMP8 mice. To establish the model of knockdown of nuclear receptor subfamily 4 group A member 1 (Nr4a1), AAV9-Nr4a1-RNAi was injected into the hippocampi of SAMP8 mice. In the C57BL/6J mice with YAP1 knockdown, Nr4a1 expression was either knocked down or inhibited with DIM-C to examine the impact of Nr4a1 on tau phosphorylation and cognitive deficits. Primary hippocampal neurons from Sprague-Dawley (SD) rats were infected with lentivirus (LV)-YAP1 to create a YAP1 overexpression model, and Aβ treatment was used to induce neuronal senescence. Protein levels were assessed using immunofluorescence, Western blotting, and ELISA. Animal behavior was evaluated using the Morris water maze test, novel object recognition test, and open field test.</p><p><strong>Results: </strong>YAP1 was reduced in the hippocampus of both aged C57BL/6J mice and SAMP8 AD model mice through Hippo pathway activation, as well as in Aβ-induced senescent neurons. Overexpression of YAP1 in primary neurons significantly mitigated the Aβ-induced neuronal senescence by downregulating several senescence-related genes, including p16 and p53. The levels of phosphorylated AKT/GSK-3β in neurons were increased with overexpression of YAP1 both in vivo and in vitro. Knockdown of YAP1 induced AD-like symptoms and exacerbated cognitive decline in 2-month-old C57BL/6J mice. Injection of AAV9-YAP1 in the brains of SAMP8 mice partially alleviated neuronal senescence and enhanced cognitive function. Notably, genetic knockdown and chemical inhibition of Nr4a1 significantly ameliorated cognitive deficits as well as AD-like pathology in these subjects.</p><p><strong>Conclusions: </strong>These findings reveal an etiopathogenic relationship between aging and AD, which is associated with the YAP1-Nr4a1-AKT/GSK-3β signaling pathway. Our findings provide insight into the therapeutic strategies aimed at delaying brain aging and combating neurodegenerative diseases such as AD.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"14 1","pages":"29"},"PeriodicalIF":10.8,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12135490/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144226811","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 genome-wide RNA interference screening reveals protectiveness of SNX5 knockdown in a Parkinson's disease cell model.","authors":"Matthias Höllerhage, Linghan Duan, Oscar Wing Ho Chua, Claudia Moebius, Svenja H Bothe, Kristina Losse, Rebecca Kotzur, Kristina Lau, Franziska Hopfner, Franziska Richter, Christian Wahl-Schott, Marc Bickle, Günter U Höglinger","doi":"10.1186/s40035-025-00486-5","DOIUrl":"10.1186/s40035-025-00486-5","url":null,"abstract":"<p><strong>Background: </strong>Alpha-synuclein (αSyn) is a major player in the pathophysiology of synucleinopathies, which include Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. To date, there is no disease-modifying therapy available for these synucleinopathies. Furthermore, the intracellular mechanisms by which αSyn confers toxicity are not yet fully understood. Therefore, it is of utmost importance to investigate the pathophysiology of αSyn-induced toxicity in order to identify novel molecular targets for the development of disease-modifying therapies.</p><p><strong>Methods: </strong>We performed the first genome-wide siRNA modifier screening in a human postmitotic neuronal cell model using αSyn-induced toxicity as a read-out. In a multi-step approach, we identified several genes, whose knockdown protected against αSyn-induced toxicity. The main hit was further validated by different methods, including immunofluorescence microscopy, qPCR, and Western blot. Furthermore, the main finding was confirmed in mouse primary neurons.</p><p><strong>Results: </strong>The highest protection was achieved by knockdown of SNX5, which encodes the sorting nexin 5 (SNX5) protein, a component of the retromer complex. The protective efficacy of SNX5 knockdown was confirmed with an independent siRNA system. The protective effect of SNX5 knockdown was further confirmed in primary neurons from transgenic mice, where the knockdown of SNX5 led to amelioration of decrease in synchrony that was observed in untreated and control-siRNA-treated cells. SNX5 protein is a component of the SNX-BAR (Bin/Amphiphysin/Rvs) heterodimer, which is part of the retromer complex. Extracellular αSyn and overexpression of intracellular αSyn led to fragmentation of the trans-Golgi network, which was prevented by SNX5 knockdown that led to confinement of αSyn in early endosomes.</p><p><strong>Conclusion: </strong>In summary, our data suggest that SNX5 plays an important role in the trafficking and toxicity of αSyn. Therefore, SNX5 appears to be a target of therapeutic intervention for synucleinopathies.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"14 1","pages":"27"},"PeriodicalIF":10.8,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12131658/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144209518","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":"Alterations in sleep-activity cycles and clock gene expression across the synucleinopathy spectrum.","authors":"Maria Comas, Xavier Vidal, Oliver Rawashdeh, Ronald R Grunstein, Simon J G Lewis, Elie Matar","doi":"10.1186/s40035-025-00492-7","DOIUrl":"10.1186/s40035-025-00492-7","url":null,"abstract":"","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"14 1","pages":"28"},"PeriodicalIF":10.8,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12131590/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144217024","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":"Development of human targeted extracellular vesicles loaded with shRNA minicircles to prevent parkinsonian pathology.","authors":"Maria Izco, Carlos Sola, Martin Schleef, Marco Schmeer, María de Toro, Guglielmo Verona, Estefania Carlos, Alejandro Reinares-Sebastian, Sandra Colina, Maria Eugenia Marzo-Sola, Josune Garcia-Sanmartin, Joaquín Fernández-Irigoyen, Enrique Santamaría, Rodolfo Mugica-Vidal, Javier Blesa, Lydia Alvarez-Erviti","doi":"10.1186/s40035-025-00484-7","DOIUrl":"10.1186/s40035-025-00484-7","url":null,"abstract":"<p><strong>Background: </strong>Neurological disorders are the second leading cause of death and the leading cause of disability in the world. Thus, the development of novel disease-modifying strategies is clearly warranted. We have previously developed a therapeutic approach using mouse targeted rabies virus glycoprotein (RVG) extracellular vesicles (EVs) to deliver minicircles (MCs) expressing shRNA (shRNA-MCs) to induce long-term α-synuclein down-regulation. Although the previous therapy successfully reduced the pathology, the clinical translation was extremely unlikely since they were mouse extracellular vesicles.</p><p><strong>Methods: </strong>To overcome this limitation, we developed a source of human RVG-EVs compatible with a personalized therapy using immature dendritic cells. Human peripheral blood monocytes were differentiated in vitro into immature dendritic cells, which were transfected to express the RVG peptide. RVG-EVs containing shRNA-MCs, loaded by electroporation, were injected intravenously in the α-synuclein performed fibril (PFF) mouse model. Level of α-synuclein, phosphorylated α-synuclein aggregates, dopaminergic neurons and motor function were evaluated 90 days after the treatment. To confirm that EVs derived from patients were suitable as a vehicle, proteomic analysis of EVs derived from control, initial and advanced Parkinson's disease was performed.</p><p><strong>Results: </strong>The shRNA-MCs could be successfully loaded into human RVG-EVs and downregulate α-synuclein in SH-SY5Y cells. Intravenous injection of the shRNA-MC-loaded RVG-EVs induced long-term downregulation of α-synuclein mRNA expression and protein level, decreased α-synuclein aggregates, prevented dopaminergic cell death and ameliorated motor impairment in the α-synuclein PFF mouse model. Moreover, we confirmed that the EVs from PD patients are suitable as a personalized therapeutic vehicle.</p><p><strong>Conclusion: </strong>Our study confirmed the therapeutic potential of shRNA-MCs delivered by human RVG-EVs for long-term treatment of neurodegenerative diseases. These results pave the way for clinical use of this approach.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"14 1","pages":"26"},"PeriodicalIF":10.8,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12105355/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144151274","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":"Enhanced serum-based seed amplification assay for detecting propagative α-synuclein seeds in Parkinson's disease.","authors":"Yaoyun Kuang, Hengxu Mao, Wei Dai, Tingting Gan, Hao Lin, Jin Li, Xinling Yang, Pingyi Xu","doi":"10.1186/s40035-025-00488-3","DOIUrl":"10.1186/s40035-025-00488-3","url":null,"abstract":"","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"14 1","pages":"24"},"PeriodicalIF":10.8,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12096493/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144128728","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":"Plasma proteomic signatures as predictors of dementia risk in individuals with sleep apnea: a cohort study.","authors":"Yufei Liu, Pei-Yang Gao, Zhibo Wang, Ruiyang Li, Ke Meng, Weidong Le, Yi Tang","doi":"10.1186/s40035-025-00485-6","DOIUrl":"10.1186/s40035-025-00485-6","url":null,"abstract":"","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"14 1","pages":"25"},"PeriodicalIF":10.8,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12096503/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144128729","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":"Nose-to-brain drug delivery: from bench to bedside.","authors":"Isabell Drath, Franziska Richter, Malte Feja","doi":"10.1186/s40035-025-00481-w","DOIUrl":"10.1186/s40035-025-00481-w","url":null,"abstract":"<p><p>There is increasing interest in nose-to-brain delivery as an innovative drug delivery strategy for neurodegenerative disorders such as Parkinson's or Alzheimer's disease. The unique anatomy of the nose-brain interface facilitates direct drug transport via the olfactory and trigeminal pathways to the brain, bypassing the blood-brain barrier. Different administration techniques as well as advanced drug formulations like targeted nanoparticles and thermoresponsive systems have been explored to improve the delivery efficiency and the therapeutic efficacy. This review provides an up-to-date perspective on this fast-developing field, and discusses different studies on safety and pharmacokinetic properties. A thorough evaluation of preclinical and clinical studies reveals both promises and challenges of this delivery method, highlighting approved drugs for the treatment of epilepsy and migraine that successfully utilize intranasal routes. The current landscape of research on nose-to-brain delivery is critically discussed, and a rationale is provided for ongoing research to optimize therapeutic strategies.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"14 1","pages":"23"},"PeriodicalIF":10.8,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12090632/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144102796","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":"Inhibition of SOD1 trimerization is a novel drug target for ALS disease.","authors":"Tae-Gyun Woo, Jin Han, Yuju Kim, Young Jun Hwang, Mua Lee, So-Mi Kang, Soyoung Park, Yeongseon Ji, Yeon-Ho Chung, Songyoung Baek, Eunbyeol Shin, Minju-Kim, Hyewon Jang, Yun-Jeong Shin, Yonghoon Kwon, Bae-Hoon Kim, Bum-Joon Park","doi":"10.1186/s40035-025-00483-8","DOIUrl":"https://doi.org/10.1186/s40035-025-00483-8","url":null,"abstract":"<p><strong>Background: </strong>Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that begins with motor neuron death in the spinal cord and cerebral cortex, ultimately resulting in death from respiratory distress (breathing failure). About 90% of ALS cases are sporadic, and 10% of ALS cases are of the inherited type with a genetic cause. About 150 different gene mutations have been reported so far. SOD1 is a well-identified gene associated with ALS. Indeed, SOD1 aggregation has been reported in ALS patients, but the mechanism of SOD1 aggregation remains unclear. Our previous work showed that inhibiting SOD1 aggregation with a hit compound (PRG-A-01) could reduce the SOD1-induced cytotoxicity and extend the lifespan of ALS mouse model (SOD1^G93A-Tg). However, the low bioavailability and rapid degradation of the compound in vivo necessitates the development of a more effective candidate. We generated different derivatives and finally obtained the most potential drug candidate, PRG-A-04.</p><p><strong>Methods: </strong>Neuronal cell lines were transfected with the mutant SOD1 expression vector and incubated with PRG-A-04. SOD1 aggregation was examined by SOD1 oligomerization assay, immunofluorescence and dot blot assay. The interaction between GST-conjugated SOD1 recombinant proteins and PRG-A-04 was identified using LC-MS/MS and GST pull-down assay. To check the in vivo therapeutic effect of PRG-A-04, SOD1^G93A-Tg mice were injected with PRG-A-04; then behavioral test, histological analysis and microarray were performed.</p><p><strong>Results: </strong>PRG-A-04 demonstrated favorable pharmacokinetics including high bioavailability and significant blood-brain barrier penetration. Indeed, oral administration of PRG-A-04 in ALS mouse model inhibited the aggregation of SOD1 in the spinal cord, protected against neuronal loss, and extended the lifespan of ALS mice by up to 3 weeks. In vitro, PRG-A-04 selectively bound to the mutant form of SOD1, but not the wild type, and efficiently inhibited the aggregation caused by SOD1-G147P (a SOD1 trimer stabilizer).</p><p><strong>Conclusions: </strong>Our findings underscore the potential of targeting trimeric SOD1 in ALS treatment, positioning PRG-A-04 as a strong drug candidate for both familial and sporadic ALS.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"14 1","pages":"21"},"PeriodicalIF":10.8,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12067741/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144014995","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":"Stress granules: emerging players in neurodegenerative diseases.","authors":"Lin Yuan, Li-Hong Mao, Yong-Ye Huang, Tiago F Outeiro, Wen Li, Tuane C R G Vieira, Jia-Yi Li","doi":"10.1186/s40035-025-00482-9","DOIUrl":"10.1186/s40035-025-00482-9","url":null,"abstract":"<p><p>Stress granules (SGs) are membraneless organelles formed in the cellular cytoplasm under stressful conditions through liquid-liquid phase separation (LLPS). SG assembly can be both dependent and independent of the eIF2α pathway, whereas cellular protein quality control systems mediate SG disassembly. Chaperones and specific domains of RNA-binding proteins strongly contribute to the regulation SG dynamics. Chronic stress, arising in association with aging, may promote persistent SGs that are difficult to disassemble, thereby acting as a potential pathological nidus for protein aggregation in neurodegenerative diseases (NDDs). In this review, we discuss the dynamics of SGs and the factors involved with SG assembly and disassembly. We also highlight the relationship among LLPS, SGs, and the pathogenesis of different NDDs. More importantly, we summarize SG assembly-disassembly, which may be a double-edged sword in the pathophysiology of NDDs. This review aims to provide new insights into the biology and pathology of LLPS, SGs, and NDDs.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"14 1","pages":"22"},"PeriodicalIF":10.8,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12067921/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144039231","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":"Optogenetic induction of TDP-43 aggregation impairs neuronal integrity and behavior in Caenorhabditis elegans.","authors":"Kyung Hwan Park, Euihyeon Yu, Sooji Choi, Sangyeong Kim, Chanbin Park, J Eugene Lee, Kyung Won Kim","doi":"10.1186/s40035-025-00480-x","DOIUrl":"https://doi.org/10.1186/s40035-025-00480-x","url":null,"abstract":"<p><strong>Background: </strong>Cytoplasmic aggregation of TAR DNA binding protein 43 (TDP-43) in neurons is one of the hallmarks of TDP-43 proteinopathy. Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are closely associated with TDP-43 proteinopathy; however, it remains uncertain whether TDP-43 aggregation initiates the pathology or is a consequence of it.</p><p><strong>Methods: </strong>To demonstrate the pathology of TDP-43 aggregation, we applied the optoDroplet technique in Caenorhabditis elegans (C. elegans), which allows spatiotemporal modulation of TDP-43 phase separation and assembly.</p><p><strong>Results: </strong>We demonstrate that optogenetically induced TDP-43 aggregates exhibited insolubility similar to that observed in TDP-43 proteinopathy. These aggregates increased the severity of neurodegeneration, particularly in GABAergic motor neurons, and exacerbated sensorimotor dysfunction in C. elegans.</p><p><strong>Conclusions: </strong>We present an optogenetic C. elegans model of TDP-43 proteinopathy that provides insight into the neuropathological mechanisms of TDP-43 aggregates. Our model serves as a promising tool for identifying therapeutic targets for TDP-43 proteinopathy.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"14 1","pages":"20"},"PeriodicalIF":10.8,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12001655/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144000895","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}