Phenotype-genotype association and identifying treatment strategies for COQ8A-ataxia, a rare recessive ataxia linked to CoQ10 deficiency (TREATCOQ) – TREATCOQ

COQ8A-ataxia is a rare mitochondrial disorder characterized by slowly progressive cerebellar ataxia, combined with variable features including developmental delay, cognitive impairment, epilepsy, dystonia and myopathic features. This rare ataxia is due to loss of function mutations in COQ8A, with no clear genotype-phenotype association. Although its exact biochemical function is unknown, COQ8A has recently been shown to be required to regulate Coenzyme Q biogenesis. CoQ10 functions as an essential component of the mitochondrial respiratory chain, acts as a potent antioxidant, and contributes to membrane structure. Due to the poor bioavailability of CoQ10 to the central nervous system, 50% COQ8A-ataxia patients are non-responders to CoQ10 supplementation. The two main objectives of this proposal are (i) to identify novel therapeutic molecules to treat COQ8A-ataxia using two complementary vertebrate models of the disease and (ii) to determine the pathogenic nature of missense mutation found in COQ8A-ataxia patients. Two main complementary strategies are planned: 1) We will use zebrafish to identify novel molecules for potential therapeutics through a high-throughput screen from FDA-approved drugs, and confirm their effects in murine-derived primary cell models and in vivo mouse models of the disease. 2) We plan to investigate to assess the pathogenicity of patient-derived missense mutations by using a mouse knock-in model and patient-specific allele overexpression in the developing zebrafish.