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

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 Cook, Mercedes Prudencio, Tania F. GendronJohn D. Fryer, Yongjie Zhang, Leonard Petrucelli

Research output: Contribution to journalArticlepeer-review

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 (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 C9orf72, TBK1, and TDP-43 connects three different facets of FTD-ALS into one coherent pathway.

Original languageEnglish (US)
Pages (from-to)94-99
Number of pages6
JournalScience
Volume378
Issue number6615
DOIs
StatePublished - Oct 7 2022

ASJC Scopus subject areas

  • General

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