Modeling human coasy mutations in yeast Saccharomyces cerevisiae

Neurodegeneration with brain iron accumulation (NBIA) comprehends a wide spectrum of clinically and genetically heterogeneuos diseases characterized by neurodegeneration and iron overload in specific brain areas. Mutations in PANK2, encoding for the mitochondrial enzyme panthotenate kinase 2 which catalyzes the first step in the Coenzyme A (CoA) biosynthesis, account for about 50% of NBIA cases. Coenzyme A (CoA) is a key metabolite in all living organisms being involved in several metabolic processes including metabolism of fatty acids, carbohydrates, amino acids and ketone bodies. Recently Coenzyme A synthase (COASY) gene has been identified as a novel NBIA-associated gene, supporting the concept that a dysfunction in CoA synthesis may play a role in the pathogenesis of NBIA. To gain more insights into the potential role of CoA in NBIA and of its relationship with brain iron accumulation, we have developed a yeast model that expresses a pathogenic COASY mutation found in patients. In this model phenotypic and biochemical investigation such as measurement of the CoA levels, assessment of OXPHOS, sensitivity to oxidative stress has been performed.