Flavonoids as Potential Drugs for -Dependent Rare Neurodegenerative Diseases.

Several rare neurodegenerative diseases, including chorea acanthocytosis, are caused by mutations in the - genes. Only symptomatic treatments for these diseases are available. contains a unique gene and the yeast Δ 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 Δ 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. The gene, which encodes an iron transporter, was found to be a multicopy suppressor of Δ, pointing out the importance of iron in response to SDS stress. The growth defect of Δ 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 Δ may help to better understand --dependent pathogenesis and to develop novel therapeutic strategies.