biostudies-literatureShao WNIA NIH HHSNINDS NIH HHS94-99https://www.ebi.ac.uk/biostudies/studies/S-EPMC9942492biostudies-literatureUnknown378(6615)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 impoScience (New York, N.Y.)Two FTD-ALS genes converge on the endosomal pathway to induce TDP-43 pathology and degeneration.PMC9942492R01 AG063780RF1 AG062077U54 NS123743RF1 AG062171R01 NS117461P01 NS084974P01 AG019724RF1 NS120992R35 NS097273Dickson DWJansen-West KPark JKurti AYue MZanetti Alepuz DPrudencio MTodd TWKoike YOskarsson BGendron TFZhang YJShao WDaughrity LMDel Rosso GDunmore JAFryer JDTong JCastanedes-Casey MCook CNJones CYWu YPetrucelli LfalseTwo FTD-ALS genes converge on the endosomal pathway to induce TDP-43 pathology and degeneration.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 impo2022-01-01T00:00:00Z2022 Oct2025-04-22T09:58:38.36Z2025-04-05T23:16:59.663ZS-EPMC99424923620157310.1126/science.abq7860