NIH Research Festival
Mutations in the mitochondrial protein CHCHD10 cause autosomal dominant neuromuscular disorders including frontotemporal dementia (FTD)/ALS, mitochondrial myopathy, lower motor neuronopathy (SMAJ, spinal muscular atrophy Jokela type), and a familial form of ALS. These mutations have a strict genotype-phenotype relationship, with the p.G58R mutation causing a pure myopathy and the p.G66V mutation causing a pure lower motor neuronopathy. The molecular basis for this genotype-phenotype relationship is not well understood, and the current model of pathogenicity is toxic gain-of-function, as CHCHD10 knock-in mice but not CHCHD10 KO mice recapitulate the myopathy phenotype seen in patients with the p.G58R or p.S59L variants, as demonstrated by our lab and others. To better understand the genotype-phenotype relationship among CHCHD10 mutations, we are using a robust DOX-inducible system of differentiation of human wild type iPS (induced pluripotent stem) cells into motor neurons and myocytes. After inducing mitochondrial stress, we measured the transcriptional signature of these cells. Using CRISPR Cas9, we‚Äôve generated an allelic series of iPS cells with the homozygous pathogenic CHCHD10 mutations p.R15L, p.S59L, p.G58R, and p.G66V, as well as CHCHD10 knock-out (KO), that we will differentiate into motor neurons and myocytes to compare transcriptional signatures between mutant lines. Finally, by designing non-allele-specific antisense oligonucleotides (ASOs) targeting CHCHD10 mRNA, we are developing an effective therapy that can target diseased tissues like skeletal muscle and motor neurons. We have screened and identified several ASO candidates that are effective in knocking down CHCHD10.
Scientific Focus Area: Cell Biology
This page was last updated on Monday, September 25, 2023