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

C9 orf 72基因中的扩展GGGGCC（G4 C2）六核苷酸重复序列最近被鉴定为 肌萎缩侧索硬化症（ALS）和额颞叶痴呆症（FTD）最常见的遗传原因， 遗传和病理重叠的神经退行性疾病。介导的重复RNA毒性 据认为，隔离关键RNA结合蛋白在c9 ALS/FTD发病机制中起关键作用。然而，在这方面， 哪种RNA结合蛋白可能被长G4 C2重复RNA螯合仍然是未知的。我们建议 使用疾病相关重复序列长度和细胞模型鉴定c9 ALS/FTD中的RNA-蛋白质相互作用， 与（TG 3C 2）重复序列的相互作用蛋白质相比，类似的重复扩增导致临床上 脊髓小脑性共济失调36型（SCA 36）。通过G4 C2鉴定的RNA结合蛋白 将在c9 ALS/FTD患者死后脑样本中进一步验证重复序列，并将其功能 在iPS衍生的运动神经元和小鼠中研究。该提案的结果将为以下方面提供新的见解： 导致c9 ALS/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.