1. Two FTD-ALS genes converge on the endosomal pathway to induce TDP-43 pathology and degeneration.
- Author
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Shao W, Todd TW, Wu Y, Jones CY, Tong J, Jansen-West K, Daughrity LM, Park J, Koike Y, Kurti A, Yue M, Castanedes-Casey M, Del Rosso G, Dunmore JA, Zanetti Alepuz D, Oskarsson B, Dickson DW, Cook CN, Prudencio M, Gendron TF, Fryer JD, Zhang YJ, and Petrucelli L
- Subjects
- Animals, Mice, DNA Repeat Expansion, Endosomes metabolism, Mutation, Disease Models, Animal, Amyotrophic Lateral Sclerosis genetics, Amyotrophic Lateral Sclerosis metabolism, C9orf72 Protein genetics, C9orf72 Protein metabolism, DNA-Binding Proteins genetics, DNA-Binding Proteins metabolism, Frontotemporal Dementia genetics, Frontotemporal Dementia metabolism, Protein Serine-Threonine Kinases genetics, Protein Serine-Threonine Kinases metabolism
- 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.- Published
- 2022
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