收稿日期: 2022-01-10
录用日期: 2022-06-14
网络出版日期: 2022-12-02
基金资助
国家自然科学基金(81901162);上海市青年科技启明星计划(20QA1406300)
Initiation and regulatory mechanism of C9ORF72 (G4C2)n RAN translation
Received date: 2022-01-10
Accepted date: 2022-06-14
Online published: 2022-12-02
Supported by
National Natural Science Foundation of China(81901162);Shanghai Rising-Star Program(20QA1406300)
作为微卫星重复扩增疾病的主要致病机制之一，异常扩增的DNA重复序列通过重复序列介导的不依赖AUG （repeat associated non-AUG，RAN）翻译产生毒性蛋白，进而造成神经元死亡。肌萎缩侧索硬化（amyotrophic lateral sclerosis，ALS）是最常见的运动神经元退行性疾病，额颞叶痴呆（frontotemporal dementia，FTD）则是继阿尔茨海默病之后最常见的痴呆综合征。C9ORF72基因中GGGGCC重复序列［GGGGCC repeat，(G4C2)n］异常扩增突变是导致遗传性ALS/FTD发生的最常见的突变类型。C9ORF72 (G4C2)n异常扩增的致病机制通常被认为有3种：① C9ORF72 (G4C2)n异常扩增抑制C9ORF72基因转录，导致C9ORF72蛋白的功能缺失。② C9ORF72 (G4C2)n异常扩增形成的RNA聚集体，与多种RNA结合蛋白（RNA binding protein，RBP）发生不可逆结合，导致这些RBP的功能缺失。③由C9ORF72 (G4C2)n异常扩增形成的重复序列经RAN翻译产生多聚二肽重复蛋白（dipeptide repeat protein，DPR），导致其获得了细胞毒性。目前，越来越多的证据提示C9ORF72 (G4C2)n RAN翻译在ALS/FTD疾病的发生发展中扮演重要角色。然而，C9ORF72 (G4C2)n RAN翻译的起始及其调控机制仍不清楚。阐明C9ORF72 (G4C2)n RAN翻译的分子机制、探索以RAN翻译为靶点延缓疾病发生发展的可行性是目前该领域内的研究热点及难点。该文重点综述了C9ORF72 (G4C2)n RAN翻译的起始和调控机制相关研究的最新进展，并在此基础上探讨以C9ORF72 (G4C2)n RAN翻译为靶点降低细胞毒性、减缓神经元死亡的可行性。
冯奕源 , 徐忠匀 , 丁琳 , 尹雅芙 , 王辉 , 程维维 . C9ORF72 （G4C2）n RAN翻译的起始及其调控机制[J]. 上海交通大学学报（医学版）, 2022 , 42(10) : 1482 -1489 . DOI: 10.3969/j.issn.1674-8115.2022.10.015
As one of the main pathogenic mechanisms of the microsatellite repeat expansion diseases, the repeats from the abnormal DNA expansion produce toxic proteins through repeat-associated non-AUG (RAN) translation, which can causes neuronal death. Amyotrophic lateral sclerosis (ALS) is the most common neurodegenerative disease affecting motor neurons, while frontotemporal dementia (FTD) is a less common early-onset dementia compared to Alzheimer′s disease. C9ORF72 (G4C2)n abnormal expansion is the most common cause of ALS/FTD. Three mechanisms have been proposed for abnormal expansion of (G4C2)n in C9ORF72: ① The C9ORF72 loss-of-function results from the transcription suppression of C9ORF72 caused by the abnormal expansion of (G4C2)n in C9ORF72. ② The RNA foci from the abnormal expansion of (G4C2)n in C9ORF72, which bind to multiple RNA binding protein (RBP), lead to the dysfunction of these RBP. ③ The repeats from the abnormal expansion of (G4C2)n in C9ORF72 undergoing RAN translation produce the dipeptide repeat proteins (DPRs), which results in their toxic gain-of-function. Many studies have evidenced that RAN translation plays a pivotal role in disease progression. While a lot of studies focus on the pathologic mechanism of DPRs, the initiation and regulation mechanism of C9ORF72 (G4C2)n RAN translation is unknown and severely hinders the application of RAN translation as the therapeutic target in ALS/FTD. This review summarizes the most updated literatures on initiation and regulation mechanism of C9ORF72 (G4C2)n RAN translation and discusses the feasibility of reducing cellular toxicity and increasing neuron survival by targeting C9ORF72 (G4C2)n RAN translation.
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