TDP-43 and PINK1 mediate CHCHD10 S59L mutation–induced defects in Drosophila and in vitro

Minwoo Baek, Yun-jeong Choe, Sylvie Bannwarth, Ji Hye Kim, Swati Maitra, Gerald W. Dorn, J. Paul Taylor, Veronique Paquis-Flucklinger, Nam Chul Kim

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

Abstract

Mutations in coiled-coil-helix-coiled-coil-helix domain containing 10 (CHCHD10) can cause amyotrophic lateral sclerosis and frontotemporal dementia (ALS-FTD). However, the underlying mechanisms are unclear. Here, we generate CHCH10S59L-mutant Drosophila melanogaster and HeLa cell lines to model CHCHD10-associated ALS-FTD. The CHCHD10S59L mutation results in cell toxicity in several tissues and mitochondrial defects. CHCHD10S59L independently affects the TDP-43 and PINK1 pathways. CHCHD10S59L expression increases TDP-43 insolubility and mitochondrial translocation. Blocking TDP-43 mitochondrial translocation with a peptide inhibitor reduced CHCHD10S59L-mediated toxicity. While genetic and pharmacological modulation of PINK1 expression and activity of its substrates rescues and mitigates the CHCHD10S59L-induced phenotypes and mitochondrial defects, respectively, in both Drosophila and HeLa cells. Our findings suggest that CHCHD10S59L-induced TDP-43 mitochondrial translocation and chronic activation of PINK1-mediated pathways result in dominant toxicity, providing a mechanistic insight into the CHCHD10 mutations associated with ALS-FTD.

Original languageEnglish (US)
Article number1924
JournalNature communications
Volume12
Issue number1
DOIs
StatePublished - Dec 1 2021

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