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Nature:RNAi技术 发现治疗帕金森氏病新靶点

来源:生物谷 2013-11-25 22:07

 

2013年11月26日讯 /生物谷BIOON/--近期发表在Nature杂志上的文章称,NIH科学家采用RNAi技术发现了多个可作为帕金森氏病(Parkinson’s disease,PD)治疗靶点的基因。该发现也对线粒体损伤产生的多种疾病有重要的提示意义。

该文章的通讯作者NIH研究员Richard Youle博士称,我们发现了控制线粒体处理异常功能的基因网络,该发现为开发治疗PD和其他线粒体疾病的新药开辟了新的道路。

有些PD病人会有编码parkin蛋白的基因突变。该蛋白负责为受损的线粒体贴标签,这样受损线粒体就会由溶酶体降解。而parkin突变会影响"贴标签"过程,导致不健康的线粒体在细胞内聚集。

NIH科学家使用自动仪器将RNAi转入到人类细胞内,逐个下调了近2200个基因。接着采用自动显微镜技术检测下调基因是否会影响parkin功能。他们发现了至少四个基因能够辅助parkin功能,这些基因分别是TOMM7, HSPAI1L, BAG4和SIAH3。

接着科学家采用诱导多能干细胞技术产生人类神经元。在神经元中下调TOMM7基因会导致线粒体贴标签过程被抑制现象。后续实验进一步证明了这些基因有望成为治疗PD的新靶点。

Story Landis博士称,该研究表明了最新的高通量遗传学技术能够快速的揭示疾病的致病机制,我们希望该结果有助于科学家进一步开发治疗PD的药物。(生物谷Bioon.com)

doi:10.1038/nature12748

High-content genome-wide RNAi screens identify regulators of parkin upstream of mitophagy

Samuel A. Hasson, Lesley A. Kane, Koji Yamano, Chiu-Hui Huang, Danielle A. Sliter, Eugen Buehler, Chunxin Wang, Sabrina M. Heman-Ackah, Tara Hessa, Rajarshi Guha, Scott E. Martin & Richard J. Youle

An increasing body of evidence points to mitochondrial dysfunction as a contributor to the molecular pathogenesis of neurodegenerative diseases such as Parkinson’s disease1. Recent studies of the Parkinson’s disease associated genes PINK1 (ref. 2) and parkin (PARK2, ref. 3) indicate that they may act in a quality control pathway preventing the accumulation of dysfunctional mitochondria4, 5, 6, 7, 8. Here we elucidate regulators that have an impact on parkin translocation to damaged mitochondria with genome-wide small interfering RNA (siRNA) screens coupled to high-content microscopy. Screening yielded gene candidates involved in diverse cellular processes that were subsequently validated in low-throughput assays. This led to characterization of TOMM7 as essential for stabilizing PINK1 on the outer mitochondrial membrane following mitochondrial damage. We also discovered that HSPA1L (HSP70 family member) and BAG4 have mutually opposing roles in the regulation of parkin translocation. The screens revealed that SIAH3, found to localize to mitochondria, inhibits PINK1 accumulation after mitochondrial insult, reducing parkin translocation. Overall, our screens provide a rich resource to understand mitochondrial quality control.

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