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

C9orf72基因中扩展的GGGGCC(G4C2)六核苷酸重复序列最近被发现是 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 遗传和病理重叠的神经退行性疾病。基因介导的重复RNA毒杀作用 分离关键的RNA结合蛋白被认为在c9ALS/FTD的发病机制中起关键作用。然而， 目前尚不清楚哪个核糖核酸结合蛋白(S)可能被长的G4C2重复RNA所隔离。我们建议 使用与疾病相关的重复长度和细胞模型，以及通过 与(TG3C2)重复序列的相互作用蛋白相比，类似的重复序列扩张导致临床上 不同疾病脊髓小脑性共济失调36型(SCA36)。经G4C2鉴定的核糖核酸结合蛋白(S) 重复序列将在c9ALS/FTD患者的尸检脑样本中得到进一步验证，其功能将被 在iPS来源的运动神经元和小鼠身上进行了研究。这项提案的结果将为我们提供对 导致C9ALS/FTD神经变性的细胞级联反应。

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.