CHCHD10-related neurodegeneration : from gene to therapeutic approach

Description

Abstract The identification of a point mutation (p.Ser59Leu) in the CHCHD10 gene was the first genetic evidence that mitochondrial dysfunction can trigger motor neuron disease (MND). The generation of different cell models has allowed us to understand some of the steps involved in neuronal death, including the central role of the disassembly of the MItochondrial contact site and Cristae Organizing System (MICOS) complex, which leads to the destructuring of mitochondrial cristae. CHCHD10-associated diseases have a broad clinical spectrum and Chchd10S59L/+ mice recapitulate all phenotypes presented by patients with mitochondrial myopathy, cardiomyopathy and, typical MND features. Recent data show that these animals also provide a model for the frontotemporal dementia, seen in patients. Dissecting the cellular pathways disrupted by the expression of mutant CHCHD10 alleles contributes to the development of new therapeutic approaches. Using a yeast-based high-throughput drug screen to search for FDA-approved molecules that rescue the deleterious effects of MICOS disassembly, we identified nifuroxazide (NFX), an antibacterial molecule. NFX rescues the mitochondrial network fragmentation and cristae abnormalities found in CHCHD10S59L/+ patient fibroblasts. This molecule also decreases caspase-dependent death of human motor neurons derived from iPSCs carrying the p.Ser59Leu variant. The positive effects of NFX on mitochondrial settings in CHCHD10S59L/+ cells depend on KIF5B, a protein involved in mitochondrial transport, linking cristae organization and transport machinery. Our results identify NFX and selected structural analogues as potential therapeutic molecules for disorders associated with MICOS disassembly, including amyotrophic lateral sclerosis-like motor neuron disease.