Translational Neurodegeneration最新文献

{"title":"Patient-derived iPSC models of Friedreich ataxia: a new frontier for understanding disease mechanisms and therapeutic application.","authors":"Saumya Maheshwari, Gabriela Vilema-Enríquez, Richard Wade-Martins","doi":"10.1186/s40035-023-00376-8","DOIUrl":"10.1186/s40035-023-00376-8","url":null,"abstract":"<p><p>Friedreich ataxia (FRDA) is a rare genetic multisystem disorder caused by a pathological GAA trinucleotide repeat expansion in the FXN gene. The numerous drawbacks of historical cellular and rodent models of FRDA have caused difficulty in performing effective mechanistic and translational studies to investigate the disease. The recent discovery and subsequent development of induced pluripotent stem cell (iPSC) technology provides an exciting platform to enable enhanced disease modelling for studies of rare genetic diseases. Utilising iPSCs, researchers have created phenotypically relevant and previously inaccessible cellular models of FRDA. These models enable studies of the molecular mechanisms underlying GAA-induced pathology, as well as providing an exciting tool for the screening and testing of novel disease-modifying therapies. This review explores how the use of iPSCs to study FRDA has developed over the past decade, as well as discussing the enormous therapeutic potentials of iPSC-derived models, their current limitations and their future direction within the field of FRDA research.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"12 1","pages":"45"},"PeriodicalIF":12.6,"publicationDate":"2023-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10510273/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41166481","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":"Pathological insights from amyotrophic lateral sclerosis animal models: comparisons, limitations, and challenges.","authors":"Longhong Zhu, Shihua Li, Xiao-Jiang Li, Peng Yin","doi":"10.1186/s40035-023-00377-7","DOIUrl":"10.1186/s40035-023-00377-7","url":null,"abstract":"<p><p>In order to dissect amyotrophic lateral sclerosis (ALS), a multigenic, multifactorial, and progressive neurodegenerative disease with heterogeneous clinical presentations, researchers have generated numerous animal models to mimic the genetic defects. Concurrent and comparative analysis of these various models allows identification of the causes and mechanisms of ALS in order to finally obtain effective therapeutics. However, most genetically modified rodent models lack overt pathological features, imposing challenges and limitations in utilizing them to rigorously test the potential mechanisms. Recent studies using large animals, including pigs and non-human primates, have uncovered important events that resemble neurodegeneration in patients' brains but could not be produced in small animals. Here we describe common features as well as discrepancies among these models, highlighting new insights from these models. Furthermore, we will discuss how to make rodent models more capable of recapitulating important pathological features based on the important pathogenic insights from large animal models.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"12 1","pages":"46"},"PeriodicalIF":12.6,"publicationDate":"2023-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10510301/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41103368","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 dopamine in the pathophysiology of Parkinson's disease.","authors":"Zhi Dong Zhou, Ling Xiao Yi, Dennis Qing Wang, Tit Meng Lim, Eng King Tan","doi":"10.1186/s40035-023-00378-6","DOIUrl":"10.1186/s40035-023-00378-6","url":null,"abstract":"<p><p>A pathological feature of Parkinson's disease (PD) is the progressive loss of dopaminergic neurons and decreased dopamine (DA) content in the substantia nigra pars compacta in PD brains. DA is the neurotransmitter of dopaminergic neurons. Accumulating evidence suggests that DA interacts with environmental and genetic factors to contribute to PD pathophysiology. Disturbances of DA synthesis, storage, transportation and metabolism have been shown to promote neurodegeneration of dopaminergic neurons in various PD models. DA is unstable and can undergo oxidation and metabolism to produce multiple reactive and toxic by-products, including reactive oxygen species, DA quinones, and 3,4-dihydroxyphenylacetaldehyde. Here we summarize and highlight recent discoveries on DA-linked pathophysiologic pathways, and discuss the potential protective and therapeutic strategies to mitigate the complications associated with DA.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"12 1","pages":"44"},"PeriodicalIF":12.6,"publicationDate":"2023-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10506345/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10306290","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":"Research progress on the role of extracellular vesicles in neurodegenerative diseases.","authors":"Zhengzhe Li, Xiaoling Wang, Xiaoxing Wang, Xiaomei Yi, Yin Kwan Wong, Jiyang Wu, Fangfang Xie, Die Hu, Qi Wang, Jigang Wang, Tianyu Zhong","doi":"10.1186/s40035-023-00375-9","DOIUrl":"10.1186/s40035-023-00375-9","url":null,"abstract":"<p><p>Neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease, affect millions of people worldwide. Tremendous efforts have been put into disease-related research, but few breakthroughs have been made in diagnostic and therapeutic approaches. Extracellular vesicles (EVs) are heterogeneous cell-derived membrane structures that arise from the endosomal system or are directly separated from the plasma membrane. EVs contain many biomolecules, including proteins, nucleic acids, and lipids, which can be transferred between different cells, tissues, or organs, thereby regulating cross-organ communication between cells during normal and pathological processes. Recently, EVs have been shown to participate in various aspects of neurodegenerative diseases. Abnormal secretion and levels of EVs are closely related to the pathogenesis of neurodegenerative diseases and contribute to disease progression. Numerous studies have proposed EVs as therapeutic targets or biomarkers for neurodegenerative diseases. In this review, we summarize and discuss the advanced research progress on EVs in the pathological processes of several neurodegenerative diseases. Moreover, we outline the latest research on the roles of EVs in neurodegenerative diseases and their therapeutic potential for the diseases.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"12 1","pages":"43"},"PeriodicalIF":12.6,"publicationDate":"2023-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10494410/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10221039","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":"Large-scale proximity extension assay reveals CSF midkine and DOPA decarboxylase as supportive diagnostic biomarkers for Parkinson's disease.","authors":"Wojciech Paslawski, Shervin Khosousi, Ellen Hertz, Ioanna Markaki, Adam Boxer, Per Svenningsson","doi":"10.1186/s40035-023-00374-w","DOIUrl":"10.1186/s40035-023-00374-w","url":null,"abstract":"<p><strong>Background: </strong>There is a need for biomarkers to support an accurate diagnosis of Parkinson's disease (PD). Cerebrospinal fluid (CSF) has been a successful biofluid for finding neurodegenerative biomarkers, and modern highly sensitive multiplexing methods offer the possibility to perform discovery studies. Using a large-scale multiplex proximity extension assay (PEA) approach, we aimed to discover novel diagnostic protein biomarkers allowing accurate discrimination of PD from both controls and atypical Parkinsonian disorders (APD).</p><p><strong>Methods: </strong>CSF from patients with PD, corticobasal syndrome (CBS), progressive supranuclear palsy (PSP), multiple system atrophy and controls, were analysed with Olink PEA panels. Three cohorts were used in this study, comprising 192, 88 and 36 cases, respectively. All samples were run on the Cardiovascular II, Oncology II and Metabolism PEA panels.</p><p><strong>Results: </strong>Our analysis revealed that 26 and 39 proteins were differentially expressed in the CSF of test and validation PD cohorts, respectively, compared to controls. Among them, 6 proteins were changed in both cohorts. Midkine (MK) was increased in PD with the strongest effect size and results were validated with ELISA. Another most increased protein in PD, DOPA decarboxylase (DDC), which catalyses the decarboxylation of DOPA (L-3,4-dihydroxyphenylalanine) to dopamine, was strongly correlated with dopaminergic treatment. Moreover, Kallikrein 10 was specifically changed in APD compared with both PD and controls, but unchanged between PD and controls. Wnt inhibitory factor 1 was consistently downregulated in CBS and PSP patients in two independent cohorts.</p><p><strong>Conclusions: </strong>Using the large-scale PEA approach, we have identified potential novel PD diagnostic biomarkers, most notably MK and DDC, in the CSF of PD patients.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"12 1","pages":"42"},"PeriodicalIF":10.8,"publicationDate":"2023-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10476347/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10556211","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":"Early GCase activity is a predictor of long-term cognitive decline in Parkinson's disease.","authors":"Linn Oftedal, Johannes Lange, Kenn Freddy Pedersen, Aleksander Hagen Erga, Ingvild Dalen, Ole-Bjørn Tysnes, Guido Alves, Jodi Maple-Grødem","doi":"10.1186/s40035-023-00373-x","DOIUrl":"10.1186/s40035-023-00373-x","url":null,"abstract":"","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"12 1","pages":"41"},"PeriodicalIF":12.6,"publicationDate":"2023-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10463992/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10176647","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":"α-Synuclein-carrying astrocytic extracellular vesicles in Parkinson pathogenesis and diagnosis.","authors":"Pan Wang, Guoyu Lan, Bin Xu, Zhenwei Yu, Chen Tian, Xia Lei, Wassilios G Meissner, Tao Feng, Ying Yang, Jing Zhang","doi":"10.1186/s40035-023-00372-y","DOIUrl":"10.1186/s40035-023-00372-y","url":null,"abstract":"<p><strong>Background: </strong>The accumulation of α-synuclein (α-syn), an essential step in PD development and progression, is observed not only in neurons but also in glia, including astrocytes. The mechanisms regulating astrocytic α-syn level and aggregation remain unclear. More recently, it has been demonstrated that a part of α-syn spreading occurs through extracellular vesicles (EVs), although it is unknown whether this process is involved in astrocytes of PD. It is known, however, that EVs derived from the central nervous system exist in the blood and are extensively explored as biomarkers for PD and other neurodegenerative disorders.</p><p><strong>Methods: </strong>Primary astrocytes were transfected with A53T α-syn plasmid or exposed to α-syn aggregates. The level of astrocyte-derived EVs (AEVs) was assessed by nanoparticle tracking analysis and immunofluorescence. The lysosomal function was evaluated by Cathepsin assays, immunofluorescence for levels of Lamp1 and Lamp2, and LysoTracker Red staining. The Apogee assays were optimized to measure the GLT-1⁺ AEVs in clinical cohorts of 106 PD, 47 multiple system atrophy (MSA), and 103 healthy control (HC) to test the potential of plasma AEVs as a biomarker to differentiate PD from other forms of parkinsonism.</p><p><strong>Results: </strong>The number of AEVs significantly increased in primary astrocytes with α-syn deposition. The mechanism of increased AEVs was partially attributed to lysosomal dysfunction. The number of α-syn-carrying AEVs was significantly higher in patients with PD than in HC and MSA. The integrative model combining AEVs with total and aggregated α-syn exhibited efficient diagnostic power in differentiating PD from HC with an AUC of 0.915, and from MSA with an AUC of 0.877.</p><p><strong>Conclusions: </strong>Pathological α-syn deposition could increase the astrocytic secretion of EVs, possibly through α-syn-induced lysosomal dysfunction. The α-syn-containing AEVs in the peripheral blood may be an effective biomarker for clinical diagnosis or differential diagnosis of PD.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"12 1","pages":"40"},"PeriodicalIF":12.6,"publicationDate":"2023-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10463943/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10185426","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The potential impact of clinical factors on blood-based biomarkers for Alzheimer's disease.","authors":"Fengfeng Pan, Yan Lu, Qi Huang, Fang Xie, Jingye Yang, Qihao Guo","doi":"10.1186/s40035-023-00371-z","DOIUrl":"10.1186/s40035-023-00371-z","url":null,"abstract":"","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"12 1","pages":"39"},"PeriodicalIF":12.6,"publicationDate":"2023-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10436434/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10538149","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":"Multidimensional biomarkers for multiple system atrophy: an update and future directions.","authors":"Linlin Wan,&nbsp;Sudan Zhu,&nbsp;Zhao Chen,&nbsp;Rong Qiu,&nbsp;Beisha Tang,&nbsp;Hong Jiang","doi":"10.1186/s40035-023-00370-0","DOIUrl":"https://doi.org/10.1186/s40035-023-00370-0","url":null,"abstract":"<p><p>Multiple system atrophy (MSA) is a fatal progressive neurodegenerative disease. Biomarkers are urgently required for MSA to improve the diagnostic and prognostic accuracy in clinic and facilitate the development and monitoring of disease-modifying therapies. In recent years, significant research efforts have been made in exploring multidimensional biomarkers for MSA. However, currently few biomarkers are available in clinic. In this review, we systematically summarize the latest advances in multidimensional biomarkers for MSA, including biomarkers in fluids, tissues and gut microbiota as well as imaging biomarkers. Future directions for exploration of novel biomarkers and promotion of implementation in clinic are also discussed.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"12 1","pages":"38"},"PeriodicalIF":12.6,"publicationDate":"2023-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10375766/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10281785","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":"Clinical evidence of human pathogens implicated in Alzheimer's disease pathology and the therapeutic efficacy of antimicrobials: an overview.","authors":"Celso S G Catumbela, Vijayasree V Giridharan, Tatiana Barichello, Rodrigo Morales","doi":"10.1186/s40035-023-00369-7","DOIUrl":"10.1186/s40035-023-00369-7","url":null,"abstract":"<p><p>A wealth of pre-clinical reports and data derived from human subjects and brain autopsies suggest that microbial infections are relevant to Alzheimer's disease (AD). This has inspired the hypothesis that microbial infections increase the risk or even trigger the onset of AD. Multiple models have been developed to explain the increase in pathogenic microbes in AD patients. Although this hypothesis is well accepted in the field, it is not yet clear whether microbial neuroinvasion is a cause of AD or a consequence of the pathological changes experienced by the demented brain. Along the same line, the gut microbiome has also been proposed as a modulator of AD. In this review, we focus on human-based evidence demonstrating the elevated abundance of microbes and microbe-derived molecules in AD hosts as well as their interactions with AD hallmarks. Further, the direct-purpose and potential off-target effects underpinning the efficacy of anti-microbial treatments in AD are also addressed.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"12 1","pages":"37"},"PeriodicalIF":10.8,"publicationDate":"2023-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10369764/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10245223","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}