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.
Highlights
Mutations in coiled-coil-helix-coiled-coil-helix domain containing 10 (CHCHD10) can cause amyotrophic lateral sclerosis and frontotemporal dementia (ALS-FTD)
We found that CHCHD10S59L expression imparts a toxic gain of function and that this dominant toxicity is mediated through two distinct axes: TDP-43 and PINK1
Further phylogenetic analysis with a neighborjoining tree of these genes revealed that CG5010 is the Drosophila gene sharing the highest homology with both human CHCHD2 and CHCHD10 (Supplementary Fig. 1a)
Summary
Mutations in coiled-coil-helix-coiled-coil-helix domain containing 10 (CHCHD10) can cause amyotrophic lateral sclerosis and frontotemporal dementia (ALS-FTD). 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. Bannwarth et al.[1] showed that CHCHD10 expression in patient tissues is not affected and that overexpression of CHCHD10S59L causes mitochondrial defects similar to that in affected patients This suggests that CHCHD10S59L is a dominant gain-of-function mutant. Patient fibroblasts with either CHCHD10R15L or CHCHD10G66V exhibit reduced expression and protein instability, supporting a haploinsufficiency mechanism[20,21] These data indicate that more detailed investigation is necessary to understand the disease-causing mechanism(s) of mutant CHCHD10 and suggest that CHCHD10 mutations have multiple modes of action
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