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Mechanistic insight into RNA-mediated toxicity of C9orf72-linked ALS/FTD

C9orf72 连接的 ALS/FTD 的 RNA 介导毒性的机制见解

基本信息

批准号：
10019613
负责人：
GARY J BASSELL
金额：
$ 19.13万
依托单位：
EMORY UNIVERSITY
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：
2019-09-18 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10019613
关键词：
Affinity Antisense Oligonucleotides Autopsy Biological Models Brain C9ORF72 Cell Line Cell model Clinical Dipeptides Disease Fluorescent in Situ Hybridization Genes Genetic Genetic Engineering Genomics Grant Human Engineering Immunofluorescence Immunologic In Vitro Lead Length Link MS2 coat protein Mammalian Cell Mediating Molecular Structure Motor Neurons Mus Nerve Degeneration Neurodegenerative Disorders Neurodevelopmental Disorder Neuromuscular Diseases Neurons Nuclear RNA Pathogenesis Pathogenicity Pathologic Patients Phenocopy Phenotype Physiological Play Production Protein Array Proteins Proteomics RNA RNA-Binding Proteins RNA-Protein Interaction Sampling Spinocerebellar Ataxias Spinocerebellar Degenerations Testing Time Tissue Microarray Tissues Toxic effect Translations Untranslated RNA Validation c9FTD/ALS design disease phenotype frontotemporal lobar dementia-amyotrophic lateral sclerosis gain of function induced pluripotent stem cell insight loss of function neuropathology new therapeutic target overexpression prevent protein function unpublished works

项目摘要

Expanded GGGGCC (G4C2) hexanucleotide repeats in the C9orf72 gene were recently identified as the most common genetic cause of Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD), two neurodegenerative disorders with genetic and pathological overlap. Repeat-RNA-toxicity mediated by sequestering key RNA binding proteins is thought to play key roles in c9ALS/FTD pathogenesis. However, which RNA binding protein(s) might be sequestered by long G4C2 repeat RNAs is still unknown. We propose to identify RNA-protein interactions in c9ALS/FTD using disease-relevant repeat lengths and cell models, and by comparison to interacting-proteins of (TG3C2) repeats, a similar repeat expansion that leads to a clinically disparate disease Spinocerebellar Ataxia type 36 (SCA36). The identified RNA binding protein(s) by the G4C2 repeats will be further validated in c9ALS/FTD patient postmortem brain samples and its functions will be studied in iPS-derived motor neurons and in mice. Results from this proposal will provide new insight into the cellular cascades that cause neurodegeneration in c9ALS/FTD.

C9orf72 基因中扩展的 GGGGCC (G4C2) 六核苷酸重复最近被鉴定为肌萎缩侧索硬化症（ALS）和额颞叶痴呆（FTD）最常见的遗传原因，两种具有遗传和病理重叠的神经退行性疾病。重复RNA毒性介导隔离关键 RNA 结合蛋白被认为在 c9ALS/FTD 发病机制中发挥关键作用。然而，哪些 RNA 结合蛋白可能被长 G4C2 重复 RNA 隔离仍然未知。我们建议使用疾病相关的重复长度和细胞模型来识别 c9ALS/FTD 中的 RNA-蛋白质相互作用，并通过与 (TG3C2) 重复序列的相互作用蛋白相比，类似的重复序列扩展导致临床上不同的疾病脊髓小脑性共济失调 36 型 (SCA36)。 G4C2 鉴定的 RNA 结合蛋白重复序列将在 c9ALS/FTD 患者死后脑样本中得到进一步验证，其功能将被在 iPS 衍生的运动神经元和小鼠中进行了研究。该提案的结果将为我们提供新的见解导致 c9ALS/FTD 神经变性的细胞级联反应。