Two FTD-ALS genes converge on the endosomal pathway to induce TDP-43 pathology and degeneration
Year: 2022
Type: article
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.
Source: Science
Authors: 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 N. Cook, Mercedes Prudencio, Tania F. Gendron, John D. Fryer, Yong-Jie Zhang, Leonard Petrucelli
Institutions: Mayo Clinic, Mayo Clinic in Florida, Mayo Clinic in Arizona
Language: English
Subfield: Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: G1001885234, G1888650583, G1901379026, G213847535, G418867807, G421833620, Pathobiology of Neurodegeneration in C9ORF72 repeat expansion, Nuclear Pore Complex and as a Contributor to Tau Associated Dementia, Expanding insights into FTD disease mechanisms, Frontotemporal Dementia: Genes, Images, and Emotions, Discovery of novel TDP-43 splicing targets: the Achilles heel for FTD and towards sensitive biomarkers and therapeutic targets
OpenAlex ID: W4302425342