Translational Neurodegeneration最新文献

{"title":"Refining α-synuclein seed amplification assays to distinguish Parkinson's disease from multiple system atrophy.","authors":"James A Wiseman, Clinton P Turner, Richard L M Faull, Glenda M Halliday, Birger Victor Dieriks","doi":"10.1186/s40035-025-00469-6","DOIUrl":"10.1186/s40035-025-00469-6","url":null,"abstract":"<p><strong>Background: </strong>Parkinson's disease (PD) and multiple system atrophy (MSA) are two distinct α-synucleinopathies traditionally differentiated through clinical symptoms. Early diagnosis of MSA is problematic, and seed amplification assays (SAAs), such as real-time quaking-induced conversion (RT-QuIC), offer the potential to distinguish these diseases through their underlying α-synuclein (α-Syn) pathology and proteoforms. Currently, SAAs provide a binary result, signifying either the presence or absence of α-Syn seeds. To enhance the diagnostic potential and biological relevance of these assays, there is a pressing need to incorporate quantification and stratification of α-Syn proteoform-specific aggregation kinetics into current SAA pipelines.</p><p><strong>Methods: </strong>Optimal RT-QuIC assay conditions for α-Syn seeds extracted from PD and MSA patient brains were determined, and assay kinetics were assessed for α-Syn seeds from different pathologically relevant brain regions (medulla, substantia nigra, hippocampus, middle temporal gyrus, and cerebellum). The conformational profiles of disease- and region-specific α-Syn proteoforms were determined by subjecting the amplified reaction products to concentration-dependent proteolytic digestion with proteinase K.</p><p><strong>Results: </strong>Using our protocol, PD and MSA could be accurately delineated using proteoform-specific aggregation kinetics, including α-Syn aggregation rate, maximum relative fluorescence, the gradient of amplification, and core protofilament size. MSA cases yielded significantly higher values than PD cases across all four kinetic parameters in brain tissues, with the MSA-cerebellar phenotype having higher maximum relative fluorescence than the MSA-Parkinsonian phenotype. Statistical significance was maintained when the data were analysed regionally and when all regions were grouped.</p><p><strong>Conclusions: </strong>Our RT-QuIC protocol and analysis pipeline can distinguish between PD and MSA, and between MSA phenotypes. MSA α-Syn seeds induce faster propagation and exhibit higher aggregation kinetics than PD α-Syn, mirroring the biological differences observed in brain tissue. With further validation of these quantitative parameters, we propose that SAAs could advance from a yes/no diagnostic to a theranostic biomarker that could be utilised in developing therapeutics.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"14 1","pages":"7"},"PeriodicalIF":10.8,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11804046/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143371222","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":"Second-generation anti-amyloid monoclonal antibodies for Alzheimer's disease: current landscape and future perspectives.","authors":"Byeong-Hyeon Kim, Sujin Kim, Yunkwon Nam, Yong Ho Park, Seong Min Shin, Minho Moon","doi":"10.1186/s40035-025-00465-w","DOIUrl":"10.1186/s40035-025-00465-w","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is the most common type of dementia. Monoclonal antibodies (MABs) serve as a promising therapeutic approach for AD by selectively targeting key pathogenic factors, such as amyloid-β (Aβ) peptide, tau protein, and neuroinflammation. Specifically, based on their efficacy in removing Aβ plaques from the brains of patients with AD, the U.S. Food and Drug Administration has approved three anti-amyloid MABs, aducanumab (Aduhelm®), lecanemab (Leqembi®), and donanemab (Kisunla™). Notably, lecanemab received traditional approval after demonstrating clinical benefit, supporting the Aβ cascade hypothesis. These MABs targeting Aβ are categorized based on their affinity to diverse conformational features of Aβ, including monomer, fibril, protofibril, and plaque forms of Aβ as well as pyroglutamate Aβ. First-generation MABs targeting the non-toxic monomeric Aβ, such as solanezumab, bapineuzumab, and crenezumab, failed to demonstrate clinical benefit for AD in clinical trials. In contrast, second-generation MABs, including aducanumab, lecanemab, donanemab, and gantenerumab directed against pathogenic Aβ species and aggregates have shown that reducing Aβ deposition can be an effective strategy to slow cognitive impairment in AD. In this review, we provide a comprehensive overview of the current status, mechanisms, outcomes, and limitations of second-generation MABs for the clinical treatment of AD. Moreover, we discuss the perspectives and future directions of anti-amyloid MABs in the treatment of AD.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"14 1","pages":"6"},"PeriodicalIF":10.8,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11771116/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143047804","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":"Correction: Inflammasomes in neurodegenerative diseases.","authors":"Qianchen Wang, Songwei Yang, Xuan Zhang, Shanshan Zhang, Liping Chen, Wanxue Wang, Naihong Chen, Jiaqing Yan","doi":"10.1186/s40035-025-00468-7","DOIUrl":"10.1186/s40035-025-00468-7","url":null,"abstract":"","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"14 1","pages":"5"},"PeriodicalIF":10.8,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11755795/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143029705","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":"Application of antisense oligonucleotide drugs in amyotrophic lateral sclerosis and Huntington's disease.","authors":"Kaili Ou, Qingqing Jia, Dandan Li, Shihua Li, Xiao-Jiang Li, Peng Yin","doi":"10.1186/s40035-025-00466-9","DOIUrl":"10.1186/s40035-025-00466-9","url":null,"abstract":"<p><p>Amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD) are diverse in clinical presentation and are caused by complex and multiple factors, including genetic mutations and environmental factors. Numerous therapeutic approaches have been developed based on the genetic causes and potential mechanisms of ALS and HD. Currently, available treatments for various neurodegenerative diseases can alleviate symptoms but do not provide a definitive cure. Gene therapy, which aims to modify or express specific proteins for neuroprotection or correction, is considered a powerful tool in managing neurodegenerative conditions. To date, antisense oligonucleotide (ASO) drugs targeting the pathological genes associated with ALS and HD have shown promising results in numerous animal studies and several clinical trials. This review provides a comprehensive overview of the development, mechanisms of action, limitations, and clinical applications of ASO drugs in neurodegenerative diseases, with a specific focus on ALS and HD therapeutic strategies.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"14 1","pages":"4"},"PeriodicalIF":10.8,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11748355/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143012281","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":"Correction: CD2AP deficiency aggravates Alzheimer's disease phenotypes and pathology through p38 MAPK activation.","authors":"Yan-Yan Xue, Zhe-Sheng Zhang, Rong-Rong Lin, Hui-Fen Huang, Ke-Qing Zhu, Dian-Fu Chen, Zhi-Ying Wu, Qing-Qing Tao","doi":"10.1186/s40035-024-00464-3","DOIUrl":"https://doi.org/10.1186/s40035-024-00464-3","url":null,"abstract":"","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"14 1","pages":"3"},"PeriodicalIF":10.8,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11740521/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143012285","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":"Cerebrospinal fluid cyclase-associated protein 2 is increased in Alzheimer's disease and correlates with tau pathology.","authors":"Alessandro Padovani, Andrea Pilotto, Silvia Pelucchi, Laura D'Andrea, Ramona Stringhi, Federica Gorla, Bahar Aksan, Salvatore Caratozzolo, Alberto Benussi, Alice Galli, Clara Tirloni, Daniela Mauceri, Antonio Canale, Silvana Archetti, Barbara Borroni, Monica Di Luca, Elena Marcello","doi":"10.1186/s40035-024-00462-5","DOIUrl":"https://doi.org/10.1186/s40035-024-00462-5","url":null,"abstract":"","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"14 1","pages":"1"},"PeriodicalIF":10.8,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11736935/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143012283","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":"Peripheral proteinopathy in neurodegenerative diseases.","authors":"Bin Xu, Xia Lei, Ying Yang, Jiayi Yu, Jun Chen, Zhi Xu, Keqiang Ye, Jing Zhang","doi":"10.1186/s40035-024-00461-6","DOIUrl":"10.1186/s40035-024-00461-6","url":null,"abstract":"<p><p>Proteinopathies in neurology typically refer to pathological changes in proteins associated with neurological diseases, such as the aggregation of amyloid β and Tau in Alzheimer's disease, α-synuclein in Parkinson's disease and multiple system atrophy, and TAR DNA-binding protein 43 in amyotrophic lateral sclerosis and frontotemporal dementia. Interestingly, these proteins are also commonly found in peripheral tissues, raising important questions about their roles in neurological disorders. Multiple studies have shown that peripherally derived pathological proteins not only travel to the brain through various routes, aggravating brain pathology, but also contribute significantly to peripheral dysfunction, highlighting their crucial impact on neurological diseases. Investigating how these peripherally derived proteins influence the progression of neurological disorders could open new horizons for achieving early diagnosis and treatment. This review summarizes the distribution, transportation pathways, and pathogenic mechanisms of several neurodegenerative disease-related pathological proteins in the periphery, proposing that targeting these peripheral pathological proteins could be a promising strategy for preventing and managing neurological diseases.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"14 1","pages":"2"},"PeriodicalIF":10.8,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11737199/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143012287","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-terminus α-synuclein detection reveals new and more diverse aggregate morphologies in multiple system atrophy and Parkinson's disease.","authors":"James A Wiseman, YuHong Fu, Richard L M Faull, Clinton P Turner, Maurice A Curtis, Glenda M Halliday, Birger V Dieriks","doi":"10.1186/s40035-024-00456-3","DOIUrl":"10.1186/s40035-024-00456-3","url":null,"abstract":"<p><strong>Background: </strong>Parkinson's disease (PD) and multiple system atrophy (MSA) are classified as α-synucleinopathies and are primarily differentiated by their clinical phenotypes. Delineating these diseases based on their specific α-synuclein (α-Syn) proteoform pathologies is crucial for accurate antemortem biomarker diagnosis. Newly identified α-Syn pathologies in PD raise questions about whether MSA exhibits a similar diversity. This prompted the need for a comparative study focusing on α-Syn epitope-specific immunoreactivities in both diseases, which could clarify the extent of pathological overlap and diversity, and guide more accurate biomarker development.</p><p><strong>Methods: </strong>We utilised a multiplex immunohistochemical approach to detect multiple structural domains of α-Syn proteoforms across multiple regions prone to pathological accumulation in MSA (n = 10) and PD (n = 10). Comparison of epitope-specific α-Syn proteoforms was performed in the MSA medulla, inferior olivary nucleus, substantia nigra, hippocampus, and cerebellum, and in the PD olfactory bulb, medulla, substantia nigra, hippocampus, and entorhinal cortex.</p><p><strong>Results: </strong>N-terminus and C-terminus antibodies detected significantly more α-Syn pathology in MSA than antibodies for phosphorylated (pS129) α-Syn, which are classically used to detect α-Syn. Importantly, C-terminus immunolabelling is more pronounced in MSA compared to PD. Meanwhile, N-terminus immunolabelling consistently detected the highest percentage of α-Syn across pathologically burdened regions of both diseases, which could be of biological significance. As expected, oligodendroglial involvement distinguished MSA from PD, but in contrast to PD, no substantial astrocytic or microglial α-Syn accumulation in MSA occurred. These data confirm glial-specific changes between these diseases when immunolabelling the N-terminus epitope. In comparison, N-terminus neuronal α-Syn was present in PD and MSA, with most MSA neurons lacking pS129 α-Syn proteoforms. This explains why characterisation of neuronal MSA pathologies is lacking and challenges the reliance on pS129 antibodies for the accurate quantification of α-Syn pathological load across α-synucleinopathies.</p><p><strong>Conclusions: </strong>These findings underscore the necessity of utilising a multiplex approach to detect α-Syn, most importantly including the N-terminus, to capture the entire spectrum of α-Syn proteoforms in α-synucleinopathies. The data provide novel insights toward the biological differentiation of these α-synucleinopathies and pave the way for more refined antemortem diagnostic methods to facilitate early identification and intervention of these neurodegenerative diseases.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"13 1","pages":"67"},"PeriodicalIF":10.8,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11673343/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142898467","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":"SARS-CoV-2 membrane protein induces neurodegeneration via affecting Golgi-mitochondria interaction.","authors":"Fang Wang, Hailong Han, Caifang Wang, Jingfei Wang, Yanni Peng, Ye Chen, Yaohui He, Zhouyang Deng, Fang Li, Yikang Rong, Danling Wang, Wen Liu, Hualan Chen, Zhuohua Zhang","doi":"10.1186/s40035-024-00458-1","DOIUrl":"10.1186/s40035-024-00458-1","url":null,"abstract":"<p><strong>Background: </strong>Neurological complications are a significant concern of Coronavirus Disease 2019 (COVID-19). However, the pathogenic mechanism of neurological symptoms associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is poorly understood.</p><p><strong>Methods: </strong>We used Drosophila as a model to systematically analyze SARS-CoV-2 genes encoding structural and accessory proteins and identified the membrane protein (M) that disrupted mitochondrial functions in vivo. The M protein was stereotaxically injected to further assess its effects in the brains of wild-type (WT) and 5 × FAD mice. Omics technologies, including RNA sequencing and interactome analysis, were performed to explore the mechanisms of the effects of M protein both in vitro and in vivo.</p><p><strong>Results: </strong>Systematic analysis of SARS-CoV-2 structural and accessory proteins in Drosophila identified that the M protein induces mitochondrial fragmentation and dysfunction, leading to reduced ATP production, ROS overproduction, and eventually cell death in the indirect flight muscles. In WT mice, M caused hippocampal atrophy, neural apoptosis, glial activation, and mitochondrial damage. These changes were further aggravated in 5 × FAD mice. M was localized to the Golgi apparatus and genetically interacted with four wheel drive (FWD, a Drosophila homolog of mammalian PI4KIIIβ) to regulate Golgi functions in flies. Fwd RNAi, but not PI4KIIIα RNAi, reversed the M-induced Golgi abnormality, mitochondrial fragmentation, and ATP reduction. Inhibition of PI4KIIIβ activity suppressed the M-induced neuronal cell death. Therefore, M induced mitochondrial fragmentation and apoptosis likely through disruption of Golgi-derived PI(4)P-containing vesicles.</p><p><strong>Conclusions: </strong>M disturbs the distribution and function of Golgi, leading to mitochondrial abnormality and eventually neurodegeneration via a PI4KIIIβ-mediated mechanism. This study reveals a potential mechanism for COVID-19 neurological symptoms and opens a new avenue for development of therapeutic strategies targeting SARS-CoV-2 M or mitochondria.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"13 1","pages":"68"},"PeriodicalIF":10.8,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11674522/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142898477","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":"Endosomal traffic disorders: a driving force behind neurodegenerative diseases.","authors":"Jianru Dong, Weiwei Tong, Mingyan Liu, Mengyu Liu, Jinyue Liu, Xin Jin, Ju Chen, Huachao Jia, Menglin Gao, Minjie Wei, Ying Duan, Xin Zhong","doi":"10.1186/s40035-024-00460-7","DOIUrl":"10.1186/s40035-024-00460-7","url":null,"abstract":"<p><p>Endosomes are crucial sites for intracellular material sorting and transportation. Endosomal transport is a critical process involved in the selective uptake, processing, and intracellular transport of substances. The equilibrium between endocytosis and circulation mediated by the endosome-centered transport pathway plays a significant role in cell homeostasis, signal transduction, and immune response. In recent years, there have been hints linking endosomal transport abnormalities to neurodegenerative diseases, including Alzheimer's disease. Nonetheless, the related mechanisms remain unclear. Here, we provide an overview of endosomal-centered transport pathways and highlight potential physiological processes regulated by these pathways, with a particular focus on the correlation of endosomal trafficking disorders with common pathological features of neurodegenerative diseases. Additionally, we summarize potential therapeutic agents targeting endosomal trafficking for the treatment of neurodegenerative diseases.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"13 1","pages":"66"},"PeriodicalIF":10.8,"publicationDate":"2024-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11667944/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142882671","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}