Genome-wide RNAi screen identifies the Parkinson disease GWAS risk locus SREBF1 as a regulator of mitophagy
Genome-wide RNAi screen identifies the Parkinson disease GWAS risk locus SREBF1 as a regulator of mitophagy
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DOI：
10.1073/pnas.1321207111
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发表时间：
2014-06-10
影响因子：
11.1
通讯作者：
Whitworth, Alexander J.
中科院分区：
文献类型：
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作者：
Ivatt, Rachael M.;Sanchez-Martinez, Alvaro;Whitworth, Alexander J.
帕金森病 (PD) 的遗传分析已确定了一些突变导致遗传性帕金森病的基因，以及散发性帕金森病的风险位点。 PTEN 诱导的激酶 1 (PINK1) 和 Parkin 与常染色体隐性 PD 相关，在调节线粒体自噬降解（称为线粒体自噬）的共同遗传途径中发挥作用。我们进行了全基因组 RNAi 筛选，作为一种公正的方法来识别调节 PINK1/Parkin 通路的基因。我们鉴定了几个在促进 Parkin 线粒体易位和随后的线粒体自噬中具有保守功能的基因，其中最著名的是甾醇调节元件结合转录因子 1 (SREBF1)、F-box 和 WD40 结构域蛋白 7 (FBXW7) 以及脂肪生成途径的其他成分。常染色体隐性帕金森病机制与散发性帕金森病的相关性长期以来一直存在争议。然而，随着最近将 SREBF1 确定为散发性 PD 的风险位点，我们的研究结果表明常染色体隐性遗传和散发性 PD 之间存在共同的机制联系，并强调了线粒体稳态的重要性。
Genetic analysis of Parkinson disease (PD) has identified several genes whose mutation causes inherited parkinsonism, as well as risk loci for sporadic PD. PTEN-induced kinase 1 (PINK1) and parkin, linked to autosomal recessive PD, act in a common genetic pathway regulating the autophagic degradation of mitochondria, termed mitophagy. We undertook a genome-wide RNAi screen as an unbiased approach to identify genes regulating the PINK1/Parkin pathway. We identified several genes that have a conserved function in promoting mitochondrial translocation of Parkin and subsequent mitophagy, most notably sterol regulatory element binding transcription factor 1 (SREBF1), F-box and WD40 domain protein 7 (FBXW7), and other components of the lipogenesis pathway. The relevance of mechanisms of autosomal recessive parkinsonism to sporadic PD has long been debated. However, with the recent identification of SREBF1 as a risk locus for sporadic PD, our findings suggest a common mechanistic link between autosomal recessive and sporadic PD, and underscore the importance of mitochondrial homeostasis.