Yeast and other lower eukaryotic organisms for studies of Vps13 proteins in health and disease

Abstract

Human Vps13 proteins are associated with several diseases, including the neurodegenerative disorder Chorea-acanthocytosis (ChAc). However, the biology of these proteins is relatively poorly understood. Studies in lower eukaryotic models, such as Saccharomyces cerevisiae and Dictyostelium discoideum, point to the involvement of Vps13 in many key cellular processes, the actin cytoskeleton organization, vesicular trafficking, regulation of membrane contact sites, mitochondrial functioning and autophagy. Recent findings revealed that yeast Vps13 binds phosphatidylinositol lipids via at least four different lipid binding regions. Modelling of ChAc-associated mutations in yeast has revealed that particular amino acid substitutions give rise to specific phenotypes. Noteworthy, a mutation in the APT1 domain of Vps13 results in diminished lipid binding and disturbances of all processes studied, including the actin cytoskeleton organization, vacuolar transport, endocytosis and sporulation. This review describes the great potential of simple eukaryotes to decipher disease mechanisms and highlights novel insights into the pathological role of Vps13 towards ChAc.