C9orf72
神经退行性变
坦克结合激酶1
内体
失智症
额颞叶变性
肌萎缩侧索硬化
表型
基因
生物
蛋白质聚集
细胞生物学
突变
磷酸化
蛋白激酶A
三核苷酸重复扩增
遗传学
医学
病理
痴呆
MAP激酶激酶激酶
等位基因
细胞内
疾病
作者
Wei Shao,Tiffany W. Todd,Yanwei Wu,Caroline Y. Jones,Jimei Tong,Karen Jansen‐West,Lillian M. Daughrity,Jinyoung Park,Yuka Koike,Aishe Kurti,Mei Yue,Monica Castanedes‐Casey,Giulia del Rosso,Judith A. Dunmore,Desiree Zanetti Alepuz,Björn Oskarsson,Dennis W. Dickson,Casey Cook,Mercedes Prudencio,Tania F. Gendron,John Denis Fryer,Yong‐Jie Zhang,Leonard Petrucelli
出处
期刊:Science
[American Association for the Advancement of Science (AAAS)]
日期:2022-10-07
卷期号:378 (6615): 94-99
被引量:37
标识
DOI:10.1126/science.abq7860
摘要
Frontotemporal dementia and amyotrophic lateral sclerosis (FTD-ALS) are associated with both a repeat expansion in the C9orf72 gene and mutations in the TANK-binding kinase 1 ( TBK1 ) gene. We found that TBK1 is phosphorylated in response to C9orf72 poly(Gly-Ala) [poly(GA)] aggregation and sequestered into inclusions, which leads to a loss of TBK1 activity and contributes to neurodegeneration. When we reduced TBK1 activity using a TBK1-R228H (Arg 228 →His) mutation in mice, poly(GA)-induced phenotypes were exacerbated. These phenotypes included an increase in TAR DNA binding protein 43 (TDP-43) pathology and the accumulation of defective endosomes in poly(GA)-positive neurons. Inhibiting the endosomal pathway induced TDP-43 aggregation, which highlights the importance of this pathway and TBK1 activity in pathogenesis. This interplay between C9orf72 , TBK1 , and TDP-43 connects three different facets of FTD-ALS into one coherent pathway.
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