C9orf72
失智症
三核苷酸重复扩增
神经退行性变
肌萎缩侧索硬化
翻译(生物学)
神经科学
生物
RNA结合蛋白
细胞生物学
计算生物学
核糖核酸
遗传学
疾病
医学
痴呆
基因
病理
等位基因
信使核糖核酸
作者
Hana M. Odeh,James Shorter
摘要
A hexanucleotide repeat expansion GGGGCC (G4C2) within chromosome 9 open reading frame 72 (C9orf72) is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD). This seminal realization has rapidly focused our attention to the non-canonical translation (RAN translation) of the repeat expansion, which yields dipeptide-repeat protein products (DPRs). The mechanisms by which DPRs might contribute to C9-ALS/FTD are widely studied. Arginine-rich DPRs (R-DPRs) are the most toxic of the five different DPRs produced in neurons, but how do R-DPRs promote C9-ALS/FTD pathogenesis? Proteomic analyses have uncovered potential pathways to explore. For example, the vast majority of the R-DPR interactome is comprised of disease-linked RNA-binding proteins (RBPs) with low-complexity domains (LCDs), strongly suggesting a link between R-DPRs and aberrations in liquid–liquid phase separation (LLPS). In this review, we showcase several potential mechanisms by which R-DPRs disrupt various phase-separated compartments to elicit deleterious neurodegeneration. We also discuss potential therapeutic strategies to counter R-DPR toxicity in C9-ALS/FTD.
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