Yang Qijie, Jiao Bin, Shen Lu
Department of Neurology, Xiangya Hospital, Central South University, Changsha, China.
National Clinical Research Center for Geriatric Disorders, Central South University, Changsha, China.
Front Genet. 2020 Sep 2;11:562758. doi: 10.3389/fgene.2020.562758. eCollection 2020.
The expanded GGGGCC hexanucleotide repeat in the non-coding region of the gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). There are three main disease mechanisms: loss of function of C9ORF72 protein, gain of function from the accumulation of sense and antisense (GGGGCC)n in RNA, and from the production of toxic dipeptides repeat proteins (DPRs) by non-AUG initiated translation. While many of the downstream mechanisms have been identified, the specific pathogenic pathway is still unclear. In this article, we provide an overview on the currently available literature and propose several hypotheses: (1) The pathogenesis of -associated ALS/FTD, which cannot be explained by a single mechanism, involves a dual mechanism of both loss and gain of function. (2) The loss of function and gain of function can cause TDP-43 aggregation and damage nucleocytoplasmic transport. (3) Neurodegeneration can be caused by an accumulation of toxic substances in neurons themselves. In addition, we suggest that microglia may cause neurodegeneration by releasing inflammatory factors to neurons. Finally, we summarize several of the most promising treatment strategies.
基因非编码区中扩展的GGGGCC六核苷酸重复序列是肌萎缩侧索硬化症（ALS）和额颞叶痴呆（FTD）最常见的遗传病因。存在三种主要的疾病机制：C9ORF72蛋白功能丧失、RNA中正义和反义（GGGGCC）n积累导致的功能获得，以及非AUG起始翻译产生有毒二肽重复蛋白（DPRs）。虽然已经确定了许多下游机制，但具体的致病途径仍不清楚。在本文中，我们概述了当前可用的文献并提出了几种假设：（1）与相关的ALS/FTD的发病机制不能用单一机制解释，涉及功能丧失和功能获得的双重机制。（2）功能丧失和功能获得可导致TDP-43聚集并损害核质运输。（3）神经退行性变可能由神经元自身有毒物质的积累引起。此外，我们认为小胶质细胞可能通过向神经元释放炎症因子而导致神经退行性变。最后，我们总结了几种最有前景的治疗策略。
