Department of Genetics, University of Leicester, Leicester, UK.
Nat Genet. 2013 Oct;45(10):1249-54. doi: 10.1038/ng.2732. Epub 2013 Aug 25.
Huntington's disease is a fatal neurodegenerative disorder caused by a CAG repeat expansion encoding a polyglutamine tract in the huntingtin (Htt) protein. Here we report a genome-wide overexpression suppressor screen in which we identified 317 ORFs that ameliorate the toxicity of a mutant Htt fragment in yeast and that have roles in diverse cellular processes, including mitochondrial import and copper metabolism. Two of these suppressors encode glutathione peroxidases (GPxs), which are conserved antioxidant enzymes that catalyze the reduction of hydrogen peroxide and lipid hydroperoxides. Using genetic and pharmacological approaches in yeast, mammalian cells and Drosophila, we found that GPx activity robustly ameliorates Huntington's disease-relevant metrics and is more protective than other antioxidant approaches tested here. Notably, we found that GPx activity, unlike many antioxidant treatments, does not inhibit autophagy, which is an important mechanism for clearing mutant Htt. Because previous clinical trials have indicated that GPx mimetics are well tolerated in humans, this study may have important implications for treating Huntington's disease.
亨廷顿病是一种致命的神经退行性疾病，由亨廷顿蛋白（Htt）中编码多聚谷氨酰胺链的 CAG 重复扩展引起。在这里，我们报告了一项全基因组过表达抑制剂筛选，从中我们鉴定出 317 个 ORF，这些 ORF 可改善酵母中突变型 Htt 片段的毒性，并在包括线粒体输入和铜代谢在内的多种细胞过程中发挥作用。其中两种抑制剂编码谷胱甘肽过氧化物酶（GPx），这是一种保守的抗氧化酶，可催化过氧化氢和脂质过氧化物的还原。我们在酵母、哺乳动物细胞和果蝇中使用遗传和药理学方法发现，GPx 活性可显著改善与亨廷顿病相关的指标，并且比这里测试的其他抗氧化方法更具保护作用。值得注意的是，我们发现 GPx 活性与许多抗氧化治疗不同，不会抑制自噬，自噬是清除突变型 Htt 的重要机制。由于先前的临床试验表明，GPx 模拟物在人类中具有良好的耐受性，因此这项研究可能对治疗亨廷顿病具有重要意义。
