C9orf72
三核苷酸重复扩增
肌萎缩侧索硬化
生物
应力颗粒
RNA剪接
RNA结合蛋白
细胞生物学
神经退行性变
翻译(生物学)
核糖体生物发生
遗传学
核糖体
核糖核酸
基因
医学
信使核糖核酸
病理
等位基因
疾病
作者
Zhao Zhong Chong,Daniel L. Menkes,Nizar Souayah
出处
期刊:Reviews in The Neurosciences
[De Gruyter]
日期:2023-08-02
标识
DOI:10.1515/revneuro-2023-0060
摘要
Abstract Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and fatal neurodegenerative disorder. Mutations in C9orf72 and the resulting hexanucleotide repeat (GGGGCC) expansion (HRE) has been identified as a major cause of familial ALS, accounting for about 40 % of familial and 6 % of sporadic cases of ALS in Western patients. The pathological outcomes of HRE expansion in ALS have been recognized as the results of two mechanisms that include both the toxic gain-of-function and loss-of-function of C9ORF72. The gain of toxicity results from RNA and dipeptide repeats (DPRs). The HRE can be bidirectionally transcribed into RNA foci, which can bind to and disrupt RNA splicing, transport, and translation. The DPRs that include poly-glycine-alanine, poly-glycine-proline, poly-glycine- arginine, poly-proline-alanine, and poly-proline-arginine can induce toxicity by direct binding and sequestrating other proteins to interfere rRNA synthesis, ribosome biogenesis, translation, and nucleocytoplasmic transport. The C9ORF72 functions through binding to its partners-Smith-Magenis chromosome regions 8 (SMCR8) and WD repeat-containing protein (WDR41). Loss of C9ORF72 function results in impairment of autophagy, deregulation of autoimmunity, increased stress, and disruption of nucleocytoplasmic transport. Further insight into the mechanism in C9ORF72 HRE pathogenesis will facilitate identifying novel and effective therapeutic targets for ALS.
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