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

Abstract

Frontotemporal dementia and amyotrophic lateral sclerosis (FTD-ALS) are associated with both a repeat expansion in the <i>C9orf72</i> gene and mutations in the TANK-binding kinase 1 (<i>TBK1</i>) gene. We found that TBK1 is phosphorylated in response to <i>C9orf72</i> 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 <i>C9orf72</i>, <i>TBK1</i>, and TDP-43 connects three different facets of FTD-ALS into one coherent pathway.