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Atypical TDP43 isoforrms driving neurodegeneration in FTD/ALS

非典型 TDP43 亚型导致 FTD/ALS 神经退行性变

基本信息

批准号：
10295762
负责人：
Sami Barmada
金额：
$ 39万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-12-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10295762
关键词：
ALS patients Address Affect Alternative Splicing Amino Acids Amyotrophic Lateral Sclerosis Antibodies Automobile Driving Autopsy Binding Brain C9ORF72 CRISPR/Cas technology Cell Death Cell Nucleus Characteristics Clinical Cultured Cells Data Deposition Disease Disease model Exclusion Frontotemporal Dementia Generations Genome engineering Goals Homeostasis Human Hyperactivity In Vitro Induced Mutation Induced pluripotent stem cell derived neurons Label Length Link Michigan Modeling Mutation Nerve Degeneration Neurons Nuclear Nuclear Export Nuclear Protein Pathogenesis Pathologic Pathology Pathway interactions Patients Play Prevalence Production Protein Isoforms Proteins RNA RNA Splicing RNA-Binding Proteins Reagent Reporter Rodent Specificity Stress Testing Therapeutic Time Tissues Toxic effect Transcript Universities cohort design frontotemporal lobar dementia-amyotrophic lateral sclerosis in vivo induced pluripotent stem cell locked nucleic acid mutant neuron loss neuroprotection novel novel therapeutics overexpression prevent protein TDP-43 stress granule stressor targeted treatment therapeutically effective therapy development

项目摘要

Cytosolic mislocalization of the RNA binding protein TDP43 and neuronal hyperexcitability are cardinal features of TDP43-related frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Nuclear exclusion and cytosolic deposition of TDP43 are found in over half of those with FTD, and nearly 95% of those with ALS, but the origin of these changes remains unknown. Likewise, neuronal hyperexcitability is a ubiquitous finding in FTD/ALS patients, in vivo and in vitro disease models, yet the cause and consequences of this phenomenon are unclear. Our preliminary data show for the first time an intrinsic connection between TDP43 deposition and neuronal hyperexcitabilty that may play a pivotal part in the neurodegeneration observed in TDP43-related FTD/ALS. Elevated neuronal activity upregulates an uncommon TDP43 isoform that lacks the canonical, low-complexity carboxy-terminus of the protein. Due to its active nuclear export and its ability to bind full-length (fl)TDP43, This shortened (s)TDP43 isoform is actively exported from the nucleus, accumulates in cytosolic aggregates, and sequestrates full-length (fl)TDP43, thereby recapitulating TDP43 pathology in FTD/ALS. Our central goal with this project is to determine the impact of sTDP43 in FTD/ALS pathogenesis, with a long-term objective of defining novel and effective therapeutic strategies targeting TDP43 homeostasis. We will test the hypothesis that sTDP43 drives neurodegeneration in TDP43-related FTD/ALS by three specific aims. First, we will take advantage of an sTDP43-specific antibody that we developed to determine the prevalence and distribution of sTDP43 accumulation in a large cohort of sporadic and familial FTD/ALS cases curated by the University of Michigan Brain Bank. We will also investigate the impact of sTDP43 on RNA homeostasis, and determine the relationship between sTDP43, stress, and stress granules in disease models. Lastly, we will assess the contribution of sTDP43 to neurodegeneration in rodent primary neurons and human induced pluripotent stem cell-derived neurons from patients carrying FTD/ALS-associated C9orf72 hexanucleotide expansion mutations. At the completion of these studies, we will have delineated a unique disease mechanism leading to neurodegeneration in TDP43-related FTD/ALS, and highlighted potential therapeutic approaches focusing on the abnormal activity-dependent production of toxic TDP43 isoforms.

RNA 结合蛋白 TDP43 的胞质错误定位和神经元过度兴奋是重要的 TDP43 相关的额颞叶痴呆 (FTD) 和肌萎缩侧索硬化症 (ALS) 的特征。核在超过一半的 FTD 患者中发现 TDP43 的排除和胞质沉积，其中近 95% 患有 ALS，但这些变化的起源仍不清楚。同样，神经元过度兴奋是在 FTD/ALS 患者、体内和体外疾病模型中普遍存在这一发现，但其原因和后果这种现象尚不清楚。我们的初步数据首次显示了两者之间的内在联系 TDP43沉积和神经元过度兴奋可能在神经变性中发挥关键作用在 TDP43 相关的 FTD/ALS 中观察到。神经元活动升高会上调罕见的 TDP43 亚型缺乏蛋白质的规范的、低复杂性的羧基末端。由于其积极的核出口及其结合全长 (fl)TDP43 的能力，这种缩短的 (s)TDP43 异构体主动从细胞核输出，在胞质聚集体中积累，并隔离全长 (fl)TDP43，从而重演 TDP43 FTD/ALS 的病理学。我们此项目的中心目标是确定 sTDP43 对 FTD/ALS 的影响发病机制，长期目标是确定针对 TDP43 的新颖有效的治疗策略体内平衡。我们将通过以下方式检验 sTDP43 驱动 TDP43 相关 FTD/ALS 神经退行性变的假设：三个具体目标。首先，我们将利用我们开发的 sTDP43 特异性抗体确定大量散发性和家族性人群中 sTDP43 积累的患病率和分布 FTD/ALS 案例由密歇根大学脑库策划。我们还将调查影响 sTDP43 对 RNA 稳态的影响，并确定 sTDP43、应激和应激颗粒之间的关系疾病模型。最后，我们将评估 sTDP43 对啮齿动物原发性神经变性的贡献神经元和来自携带 FTD/ALS 相关患者的人诱导多能干细胞衍生的神经元 C9orf72 六核苷酸扩展突变。完成这些研究后，我们将勾勒出一个导致 TDP43 相关 FTD/ALS 神经变性的独特疾病机制，并突出了潜力治疗方法侧重于有毒 TDP43 亚型的异常活性依赖性产生。