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, Véronique Paquis‐Flucklinger, Nam Chul Kim
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 CHCH10 S59L -mutant Drosophila melanogaster and HeLa cell lines to model CHCHD10 -associated ALS-FTD. The CHCHD10 S59L mutation results in cell toxicity in several tissues and mitochondrial defects. CHCHD10 S59L independently affects the TDP-43 and PINK1 pathways. CHCHD10 S59L expression increases TDP-43 insolubility and mitochondrial translocation. Blocking TDP-43 mitochondrial translocation with a peptide inhibitor reduced CHCHD10 S59L -mediated toxicity. While genetic and pharmacological modulation of PINK1 expression and activity of its substrates rescues and mitigates the CHCHD10 S59L -induced phenotypes and mitochondrial defects, respectively, in both Drosophila and HeLa cells. Our findings suggest that CHCHD10 S59L -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.