TDP-43 and PINK1 mediate CHCHD10S59L mutation–induced defects in Drosophila and in vitro

Minwoo Baek, Yun-Jeong Choe, Sylvie Bannwarth, JiHye Kim, Swati Maitra, Gerald W. Dorn, J. Paul Taylor, Veronique Paquis-Flucklinger and Nam Chul Kim ()
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Minwoo Baek: University of Minnesota
Yun-Jeong Choe: University of Minnesota
Sylvie Bannwarth: CHU de Nice
JiHye Kim: University of Minnesota
Swati Maitra: University of Minnesota
Gerald W. Dorn: Washington University School of Medicine
J. Paul Taylor: St. Jude Children’s Research Hospital
Veronique Paquis-Flucklinger: CHU de Nice
Nam Chul Kim: University of Minnesota

Nature Communications, 2021, vol. 12, issue 1, 1-20

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-22145-9

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