Two FTD-ALS genes converge on the endosomal pathway to induce TDP-43 pathology and degeneration
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
Abstract
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.