Citations 1
Two FTD-ALS genes converge on the endosomal pathway to induce TDP-43 pathology and degeneration
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 , Rosso, Giulia del, Dunmore, Judith A. , Alepuz, Desiree Zanetti , Oskarsson, Björn , Cook, Casey , Prudencio, Mercedes , Fryer, John Denis , Zhang, Yong‐Jie , Petrucelli, Leonard , Del Rosso, Giulia, Zanetti Alepuz, Desiree, Dickson, Dennis W , Cook, Casey N , Prudencio, Mercedes , Gendron, Tania F , Zhang, Yong-Jie , Petrucelli, Leonard , Oskarsson, Björn , Shao, Wei , Koike, Yuka , Dickson, Dennis W. , Gendron, Tania F.
Science | October 6, 2022 | Volume: 378 | Issue: 6615 | Pages: 94-99
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.