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• W2971388804 abstract "Abstract Mutations in coiled-coil-helix-coiled-coil-helix domain containing 10 ( CHCHD10 ) are a genetic cause of amyotrophic lateral sclerosis and/or frontotemporal dementia (ALS-FTD). To elucidate how mutations in CHCHD10 induce disease, we generated a Drosophila melanogaster model of CHCHD10 -mediated ALS-FTD. Expression of CHCHD10 S59L in Drosophila caused gain-of-function toxicity in eyes, motor neurons, and muscles, in addition to mitochondrial defects in flies and HeLa cells. TDP-43 and PINK1 formed two axes, driving the mutant-dependent phenotypes. CHCHD10 S59L expression increased TDP-43 insolubility and mitochondrial translocation. Blocking mitochondrial translocation with a peptide inhibitor reduced CHCHD10 S59L -mediated toxicity. PINK1 knockdown rescued CHCHD10 S59L -mediated phenotypes in Drosophila and HeLa cells. The two PINK1 substrates mitofusin and mitofilin were genetic modifiers of this phenotype. Mitofusin agonists reversed the CHCHD10 S59L -induced phenotypes in Drosophila and HeLa cells and increased ATP production in Drosophila expressing C9orf72 with expanded GGGGCC repeats. Two peptides inhibitors of PINK1 mitigated the mitochondrial defects introduced by CHCHD10 S59L expression. These findings indicate that TDP-43 mitochondrial translocation and chronic activation of PINK1-mediated pathways by CHCHD10 S59L generate dominant toxicity. Therefore, inhibiting PINK1 activity may provide a therapeutic strategy for CHCHD10 -associated disease. One Sentence Summary Inhibition of TDP-43 mitochondrial translocation or PINK1 kinase activity mitigates CHCHD10 S59L -mediated mitochondrial toxicity." @default.
• W2971388804 created "2019-09-12" @default.
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• W2971388804 date "2019-09-03" @default.
• W2971388804 modified "2023-09-25" @default.
• W2971388804 title "Dominant toxicity of ALS–FTD-associated <i>CHCHD10^S59L</i> is mediated by TDP-43 and PINK1" @default.
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• W2971388804 doi "https://doi.org/10.1101/753558" @default.
• W2971388804 hasPublicationYear "2019" @default.
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