Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Pawinskiego 5A, 02-106 Warsaw, Poland.
CNRS, Institut de Biochimie et Génétique Cellulaires, Bordeaux University, CEDEX, 33077 Bordeaux, France.
Genes (Basel). 2020 Jul 21;11(7):828. doi: 10.3390/genes11070828.
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.
几种罕见的神经退行性疾病，包括棘红细胞增多症，是由-基因突变引起的。这些疾病只能进行对症治疗。酵母Δ突变体含有一个独特的基因，已被证明是药物测试的合适模型。我们对一个药物库和一个内部天然化合物及其衍生物文库进行了筛选，以寻找能防止Δ细胞在含有十二烷基硫酸钠（SDS）的培养基中生长缺陷的分子。鉴定出了包括结合铁的类黄酮木犀草素在内的 7 种多酚。对木犀草素作用的结构-活性关系和分子机制进行了表征。编码铁转运蛋白的 基因是Δ的多拷贝抑制子，这表明铁在应对 SDS 应激中的重要性。添加铁盐也能缓解Δ在 SDS 补充培养基中的生长缺陷。抑制作用不涉及细胞抗氧化反应，因为化学抗氧化剂没有活性。我们的发现支持木犀草素和铁可能针对相同的细胞过程，可能是鞘脂的合成。揭示Δ化学和遗传抑制剂的作用机制可能有助于更好地理解 - 依赖性发病机制，并开发新的治疗策略。
