Role of the C9ORF72 Gene in the Pathogenesis of Amyotrophic Lateral Sclerosis and Frontotemporal Dementia.
Role of the C9ORF72 Gene in the Pathogenesis of Amyotrophic Lateral Sclerosis and Frontotemporal Dementia.
复制标题
C9ORF72 基因在肌萎缩侧索硬化症和额颞叶痴呆发病机制中的作用。
DOI：
10.1007/s12264-020-00567-7
复制
发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Wang Guanghui
中科院分区：
文献类型：
--
作者：
Hao Zongbing;Wang Rui;Ren Haigang;Wang Guanghui
自2011年发现C9 ORF 72基因以来，在其遗传学以及确定其在疾病模型和病理机制中的作用方面取得了巨大进展;它是肌萎缩侧索硬化症（ALS）和额颞叶痴呆（FTD）最常见的遗传原因。C9 ORF 72扩增的ALS患者表现出异质性症状。C9 ORF 72扩增携带者发病后生存期较非C9 ORF 72扩增患者短。C9 ORF 72患者的病理和临床特征已通过多种模型得到很好的模拟，包括诱导多能干细胞衍生的神经元和用细菌人工染色体构建体包埋并过表达二肽重复蛋白的转基因小鼠。与C9 ORF 72病理学相关的机制包括DNA损伤、RNA代谢改变、相分离改变和核质转运受损，这可能是C9 ORF 72扩增相关ALS/FTD的基础，并为了解非C9 ORF 72扩增相关ALS、FTD和其他神经退行性疾病提供了线索。
Since the discovery of theC9ORF72gene in 2011, great advances have been achieved in its genetics and in identifying its role in disease models and pathological mechanisms; it is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). ALS patients withC9ORF72expansion show heterogeneous symptoms. Those who areC9ORF72expansion carriers have shorter survival after disease onset than non-C9ORF72expansion patients. Pathological and clinical features ofC9ORF72patients have been well mimickedviaseveral models, including induced pluripotent stem cell-derived neurons and transgenic mice that were embedded with bacterial artificial chromosome construct and that overexpressing dipeptide repeat proteins. The mechanisms implicated inC9ORF72pathology include DNA damage, changes of RNA metabolism, alteration of phase separation, and impairment of nucleocytoplasmic transport, which may underlieC9ORF72expansion-related ALS/FTD and provide insight into non-C9ORF72expansion-related ALS, FTD, and other neurodegenerative diseases.