Yeast as a Model to Find New Drugs and Drug Targets for VPS13-Dependent Neurodegenerative Diseases

Mutations in human VPS13A-D genes result in rare neurological diseases, including chorea-acanthocytosis. The pathogenesis of these diseases is poorly understood, and no effective treatment is available. As VPS13 genes are evolutionarily conserved, the effects of the pathogenic mutations could be studied in model organisms, including yeast, where one VPS13 gene is present. In this review, we summarize advancements obtained using yeast. In recent studies, vps13 Delta and vps13-I2749 yeast mutants, which are models of chorea-acanthocytosis, were used to screen for multicopy and chemical suppressors. Two of the suppressors, a fragment of the MYO3 and RCN2 genes, act by downregulating calcineurin activity. In addition, vps13 Delta suppression was achieved by using calcineurin inhibitors. The other group of multicopy suppressors were genes: FET4, encoding iron transporter, and CTR1, CTR3 and CCC2, encoding copper transporters. Mechanisms of their suppression rely on causing an increase in the intracellular iron content. Moreover, among the identified chemical suppressors were copper ionophores, which require a functional iron uptake system for activity, and flavonoids, which bind iron. These findings point at areas for further investigation in a higher eukaryotic model of VPS13-related diseases and to new therapeutic targets: calcium signalling and copper and iron homeostasis. Furthermore, the identified drugs are interesting candidates for drug repurposing for these diseases.

Automated summary

Mutations in VPS13A-D genes in humans lead to rare neurological diseases, such as chorea-acanthocytosis, with unknown pathogenesis and no effective treatment. Yeast is used as a model organism to study the effects of these pathogenic mutations. In recent studies, yeast mutants vps13 Delta and vps13-I2749, serving as models for chorea-acanthocytosis, were used to screen for multicopy and chemical suppressors. Several suppressors were identified, including genes involved in calcium signaling and iron and copper homeostasis. These findings provide insights for further investigation in higher eukaryotes and potential therapeutic targets for VPS13-related diseases.