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TDP-43 and PINK1 mediate CHCHD10^S59L mutation-induced defects in Drosophila and in vitro.

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.

SUBMITTER: Baek M

PROVIDER: S-EPMC7997989 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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

Baek Minwoo M Choe Yun-Jeong YJ Bannwarth Sylvie S Kim JiHye J Maitra Swati S Dorn Gerald W GW Taylor J Paul JP Paquis-Flucklinger Veronique V Kim Nam Chul NC

Nature communications 20210326 1

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 an ...[more]

PMID: 33772006

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Project description:Mutations in CHCHD10, a gene coding for a mitochondrial intermembrane space protein, are associated with Frontotemporal dementia (FTD)-Amyotrophic lateral sclerosis (ALS) spectrum disorders, which are pathologically characterized by cytoplasmic inclusions containing TDP-43. FTD/ALS-linked CHCHD10 mutations and TDP-43 inclusions similarly induce mitochondrial defects in respiration, fusion/fission, mtDNA stability, and cristae structure, while sizeable amounts of cytoplasmic TDP-43 aggregates are found in mitochondria. However, the mechanistic link between CHCHD10 and TDP-43 pathogenesis remains unclear. In this study, we present immunohistochemical and biochemical evidence demonstrating that insoluble CHCHD10 aggregates accumulate and colocalize with phospho-TDP-43 inclusions in brains of FTLD-TDP and AD patients, and that insoluble CHCHD10 levels tightly correlate with insoluble TDP-43 levels in control and FTLD-TDP brains. In an experimental exploration of this pathological phenotype, transgenic mice neuronally expressing FTD/ALS-linked CHCHD10R15L or CHCHDS59L mutations but not CHCHD10WT transgenic mice exhibit significantly increased CHCHD10 aggregation and phospho-TDP-43 pathology, which often colocalize within the same inclusions. Such pathologies are reflected in poor functional outcomes in long-term synaptic plasticity, motor unit physiology, and behavior in CHCHD10R15L and CHCHDS59L transgenic mice. In contrast, expression of CHCHD10WT in hTDP-43 transgenic mice (TAR4;CHCHD10WT) significantly mitigates phospho-TDP-43 pathology and rescues TDP-43-induced impairments in synaptic integrity and long-term synaptic plasticity. In isolated mitochondria, the S59L mutation induces the aggregation of resident CHCHD10S59L protein as well as the aggregation and slower turnover of recombinant TDP-43 imported into mitochondria. Likewise, in an in vitro cell-free system, the S59L mutation induces the aggregation of CHCHD10S59L protein while simultaneously enhancing the aggregation of recombinant TDP-43, as evidenced by filter trap assays and atomic force microscopy. In contrast, recombinant CHCHD10WT inhibits the growth of TDP-43 aggregates. These results in human brains, transgenic mice, and in vitro systems substantiate the role of wild type and mutant CHCHD10 in modulating mitochondrial CHCHD10 and TDP-43 pathogenesis together with associated phenotypes in long-term synaptic plasticity and motor unit physiology in mice and humans.

Dataset Information

TDP-43 and PINK1 mediate CHCHD10^S59L mutation-induced defects in Drosophila and in vitro.

Publications

TDP-43 and PINK1 mediate CHCHD10<sup>S59L</sup> mutation-induced defects in Drosophila and in vitro.

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