Translational Neurodegeneration最新文献

{"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}

{"title":"Gene therapy breakthroughs in ALS: a beacon of hope for 20% of ALS patients.","authors":"Qingjian Xie, Kezheng Li, Yinuo Chen, Yaojia Li, Wenhua Jiang, Wen Cao, Huan Yu, Dongsheng Fan, Binbin Deng","doi":"10.1186/s40035-025-00477-6","DOIUrl":"https://doi.org/10.1186/s40035-025-00477-6","url":null,"abstract":"<p><p>Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease that remains incurable. Although the etiologies of ALS are diverse and the precise pathogenic mechanisms are not fully understood, approximately 20% of ALS cases are caused by genetic factors. Therefore, advancing targeted gene therapies holds significant promise, at least for the 20% of ALS patients with genetic etiologies. In this review, we summarize the main strategies and techniques of current ALS gene therapies based on ALS risk genes, and review recent findings from animal studies and clinical trials. Additionally, we highlight ALS-related genes with well-understood pathogenic mechanisms and the potential of numerous emerging gene-targeted therapeutic approaches for ALS.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"14 1","pages":"19"},"PeriodicalIF":10.8,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12001736/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144039683","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":"Progranulin deficiency in the brain: the interplay between neuronal and non-neuronal cells.","authors":"Katarzyna Gaweda-Walerych, Vanessa Aragona, Simona Lodato, Emilia J Sitek, Ewa Narożańska, Emanuele Buratti","doi":"10.1186/s40035-025-00475-8","DOIUrl":"https://doi.org/10.1186/s40035-025-00475-8","url":null,"abstract":"<p><p>Heterozygous mutations in GRN gene lead to insufficient levels of the progranulin (PGRN) protein, resulting in frontotemporal dementia (FTD) with TAR DNA-binding protein 43 (TDP-43) inclusions, classified pathologically as frontotemporal lobar degeneration (FTLD-TDP). Homozygous GRN mutations are exceedingly rare and cause neuronal ceroid lipofuscinosis 11, a lysosomal storage disease with onset in young adulthood, or an FTD syndrome with late-onset manifestations. In this review, we highlight the broad spectrum of clinical phenotypes associated with PGRN deficiency, including primary progressive aphasia and behavioral variant of frontotemporal dementia. We explore these phenotypes alongside relevant rodent and in vitro human models, ranging from the induced pluripotent stem cell-derived neural progenitors, neurons, microglia, and astrocytes to genetically engineered heterotypic organoids containing both neurons and astrocytes. We summarize advantages and limitations of these models in recapitulating the main FTLD-GRN hallmarks, highlighting the role of non-cell-autonomous mechanisms in the formation of TDP-43 pathology, neuroinflammation, and neurodegeneration. Data obtained from patients' brain tissues and biofluids, in parallel with single-cell transcriptomics, demonstrate the complexity of interactions among the highly heterogeneous cellular clusters present in the brain, including neurons, astrocytes, microglia, oligodendroglia, endothelial cells, and pericytes. Emerging evidence has revealed that PGRN deficiency is associated with cell cluster-specific, often conserved, genetic and molecular phenotypes in the central nervous system. In this review, we focus on how these distinct cellular populations and their dysfunctional crosstalk contribute to neurodegeneration and neuroinflammation in FTD-GRN. Specifically, we characterize the phenotypes of lipid droplet-accumulating microglia and alterations of myelin lipid content resulting from lysosomal dysfunction caused by PGRN deficiency. Additionally, we consider how the deregulation of glia-neuron communication affects the exchange of organelles such as mitochondria, and the removal of excess toxic products such as protein aggregates, in PGRN-related neurodegeneration.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"14 1","pages":"18"},"PeriodicalIF":10.8,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12001433/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144062230","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":"Nootropic foods in neurodegenerative diseases: mechanisms, challenges, and future.","authors":"Le Anh Minh Nguyen, Courtney Wayne Simons, Raymond Thomas","doi":"10.1186/s40035-025-00476-7","DOIUrl":"10.1186/s40035-025-00476-7","url":null,"abstract":"<p><p>Neurodegenerative diseases (NDDs) such as Alzheimer's and Parkinson's disease are increasing globally and represent a significant cause of age-related death in the population. Recent studies emphasize the strong association between environmental stressors, particularly dietary factors, and brain health and neurodegeneration unsatisfactory outcomes. Despite ongoing efforts, the efficiency of current treatments for NDDs remains wanting. Considering this, nootropic foods with neuroprotective effects are of high interest as part of a possible long-term therapeutic strategy to improve brain health and alleviate NDDs. However, since it is a new and emerging area in food and neuroscience, there is limited information on mechanisms and challenges to consider for this to be a successful intervention. Here, we seek to address these gaps by presenting a comprehensive review of possible pathways or mechanisms including mutual interactions governing nootropic food metabolism, linkages of the pathways with NDDs, intake, and neuroprotective properties of nootropic foods. We also discuss in-depth intervention with nootropic compounds and dietary patterns in NDDs, providing a detailed exploration of their mechanisms of action. Additionally, we analyze the demand, challenges, and future directions for successful development of nootropic foods targeting NDDs.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"14 1","pages":"17"},"PeriodicalIF":10.8,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11967161/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143773257","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}