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.
Bibliographical noteFunding Information:
We thank the Bloomington Drosophila Stock Center, the VDRC Stock Center for fly lines, the IRCAN’s Molecular and Cellular Core Imaging (PICMI) facility, and the Research Instrumentation Lab at the University of Minnesota Duluth for assistance. We also thank undergraduate volunteers, Sierra Skudlarek, Austin Kurtz, Anna Huy, and Maddie Chalmers, helping in Drosophila maintenance and plasmids preparation. This work was supported by grants from the Muscular Dystrophy Association, the Wallin neuroscience discovery fund, the Engebretson Drug Design and Discovery Grant, and the NINDS/NIA 1R56NS112296-01 to N.C.K.
© 2021, The Author(s).