Science (New York, N.Y.) · 2022
Two FTD-ALS genes converge on the endosomal pathway to induce TDP-43 pathology and degeneration.
СтатьяНазвание и аннотация: Перевод пока не подготовлен
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Shao Wei, Todd Tiffany W, Wu Yanwei, Jones Caroline Y, Tong Jimei, Jansen-West Karen, Daughrity Lillian M, Park Jinyoung, Koike Yuka, Kurti Aishe, Yue Mei, Castanedes-Casey Monica, Del Rosso Giulia, Dunmore Judith A, Zanetti Alepuz Desiree, Oskarsson Björn, Dickson Dennis W, Cook Casey N, Prudencio Mercedes, Gendron Tania F, Fryer John D, Zhang Yong-Jie, Petrucelli Leonard
Аннотация
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 (Arg228→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.