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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：
10534172
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/10534172
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 Cytoplasm Data Deposition Disease Disease model Disparate 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.

胞质中RNA结合蛋白TDP43的错定位和神经元的高兴奋性是主要原因