Flavonoids as Potential Drugs for VPS13-Dependent Rare Neurodegenerative Diseases

Several rare neurodegenerative diseases, including chorea acanthocytosis, are caused by mutations in the VPS13A-Dgenes. Only symptomatic treatments for these diseases are available.Saccharomyces cerevisiaecontains a unique VPS13gene and the yeast vps13 Delta mutant has been proven as a suitable model for drug tests. A library of drugs and an in-house library of natural compounds and their derivatives were screened for molecules preventing the growth defect of vps13 Delta cells on medium with sodium dodecyl sulfate (SDS). Seven polyphenols, including the iron-binding flavone luteolin, were identified. The structure-activity relationship and molecular mechanisms underlying the action of luteolin were characterized. TheFET4gene, which encodes an iron transporter, was found to be a multicopy suppressor of vps13 Delta, pointing out the importance of iron in response to SDS stress. The growth defect of vps13 Delta in SDS-supplemented medium was also alleviated by the addition of iron salts. Suppression did not involve cell antioxidant responses, as chemical antioxidants were not active. Our findings support that luteolin and iron may target the same cellular process, possibly the synthesis of sphingolipids. Unveiling the mechanisms of action of chemical and genetic suppressors of vps13 Delta may help to better understand VPS13A-D-dependent pathogenesis and to develop novel therapeutic strategies.