{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Shao W"],"funding":["NIA NIH HHS","NINDS NIH HHS"],"pagination":["94-99"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC9942492"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["378(6615)"],"pubmed_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 (Arg<sup>228</sup>→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 impo"],"journal":["Science (New York, N.Y.)"],"pubmed_title":["Two FTD-ALS genes converge on the endosomal pathway to induce TDP-43 pathology and degeneration."],"pmcid":["PMC9942492"],"funding_grant_id":["R01 AG063780","RF1 AG062077","U54 NS123743","RF1 AG062171","R01 NS117461","P01 NS084974","P01 AG019724","RF1 NS120992","R35 NS097273"],"pubmed_authors":["Dickson DW","Jansen-West K","Park J","Kurti A","Yue M","Zanetti Alepuz D","Prudencio M","Todd TW","Koike Y","Oskarsson B","Gendron TF","Zhang YJ","Shao W","Daughrity LM","Del Rosso G","Dunmore JA","Fryer JD","Tong J","Castanedes-Casey M","Cook CN","Jones CY","Wu Y","Petrucelli L"],"additional_accession":[]},"is_claimable":false,"name":"Two FTD-ALS genes converge on the endosomal pathway to induce TDP-43 pathology and degeneration.","description":"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 (Arg<sup>228</sup>→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 impo","dates":{"release":"2022-01-01T00:00:00Z","publication":"2022 Oct","modification":"2025-04-22T09:58:38.36Z","creation":"2025-04-05T23:16:59.663Z"},"accession":"S-EPMC9942492","cross_references":{"pubmed":["36201573"],"doi":["10.1126/science.abq7860"]}}