C. elegans model identifies genetic modifiers of alpha-synuclein inclusion formation during aging.
C. elegans model identifies genetic modifiers of alpha-synuclein inclusion formation during aging.
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DOI：
10.1371/journal.pgen.1000027
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发表时间：
2008-03-21
期刊：
影响因子：
4.5
通讯作者：
Nollen EA
中科院分区：
文献类型：
--
作者：
van Ham TJ;Thijssen KL;Breitling R;Hofstra RM;Plasterk RH;Nollen EA
大脑中含有α-突触核蛋白的包涵体是帕金森氏病的病理标志，但这些包涵体是如何形成的，以及它与疾病的关系尚不清楚。我们开发了一种线虫模型，可以在活体动物中监测α-突触核蛋白包涵体的形成。在老年蠕虫中，包涵体含有聚集的α-突触核蛋白，类似于一种关键的病理特征。我们使用全基因组RNA干扰来识别参与包涵体形成的过程，并确定了80个基因，当被敲除时，导致包涵体数量过早增加。在内质网/高尔基复合体和囊泡室中表达的质量控制和囊泡运输基因过度表达，表明这些过程在α-突触核蛋白包涵体的形成中具有特定的作用。抑制基因包括与衰老相关的基因，如SIR-2.1/SIRT1和Lagr-1/LASS2。总之，我们的数据表明α-突触核蛋白包涵体的形成和细胞衰老之间存在联系，可能是通过膜内相关机制实现的。这些过程和基因为进一步研究疾病机制提供了一个框架，并为帕金森病和其他α-突触核蛋白相关疾病提供了候选易感基因和药物靶点。帕金森氏症是老年人第二常见的脑部疾病。它被认为是由环境和遗传因素造成的。然而，人们对涉及的基因和过程知之甚少。从病理学上讲，帕金森氏症是通过大脑中包含一种疾病特有的蛋白质：α-突触核蛋白来识别的。我们创造了一个小动物模型(线虫)，在这个模型中，我们可以跟踪活着的和老化的动物中α-突触核蛋白包裹体的形成。通过全基因组RNAi筛选，我们确定了80个表达影响包涵体形成的基因。这些基因包括进化上保守的长寿调节因子，这表明包涵体的形成与衰老的分子机制之间存在联系。我们的结果提供了对帕金森氏症在衰老过程中如何发生的精细理解，并确定了可能导致疾病易感性增加的过程和基因，这对于改进诊断和制定治疗干预策略非常重要。
Inclusions in the brain containing α-synuclein are the pathological hallmark of Parkinson's disease, but how these inclusions are formed and how this links to disease is poorly understood. We have developed a C. elegans model that makes it possible to monitor, in living animals, the formation of α-synuclein inclusions. In worms of old age, inclusions contain aggregated α- synuclein, resembling a critical pathological feature. We used genome-wide RNA interference to identify processes involved in inclusion formation, and identified 80 genes that, when knocked down, resulted in a premature increase in the number of inclusions. Quality control and vesicle-trafficking genes expressed in the ER/Golgi complex and vesicular compartments were overrepresented, indicating a specific role for these processes in α-synuclein inclusion formation. Suppressors include aging-associated genes, such as sir-2.1/SIRT1 and lagr-1/LASS2. Altogether, our data suggest a link between α-synuclein inclusion formation and cellular aging, likely through an endomembrane-related mechanism. The processes and genes identified here present a framework for further study of the disease mechanism and provide candidate susceptibility genes and drug targets for Parkinson's disease and other α-synuclein related disorders. Parkinson's disease is the second most common brain disorder of the elderly. It is thought to be caused by environmental and genetic factors. However, little is known about the genes and processes involved. Pathologically, Parkinson's disease is recognized by inclusions in the brain that contain a disease-specific protein: alpha-synuclein. We created a small animal model (C. elegans) in which we could follow the formation of alpha-synuclein inclusions in living and aging animals. With a genome-wide RNAi screen we identified 80 genes whose expression influences inclusion formation. These genes include evolutionarily conserved regulators of longevity, suggesting a link between inclusion formation and the molecular mechanism of aging. Our results offer a refined understanding of how Parkinson's disease arises during aging and we identify processes and genes that may underlie an increased susceptibility for the disease, which is important for improving diagnostics and developing strategies for therapeutic intervention.