The role of retromer in Parkinson's Disease

描述(由申请人提供)： 这项试点提案将扩展最近发现的逆转录蛋白VPS35的显性突变导致帕金森病(PD)。逆转录蛋白质参与了蛋白质从内体返回到反式高尔基体网络的运输。我们建议建立一个体外模型并进行一系列分析，以确定VPS35突变形式引起PD的分子机制(S)。为了建立模型，PD突变体VPS35蛋白将在细胞系中表达。分析将在几个层面上进行。我们将通过分析表达PD突变体VPS35的细胞中的受体循环来检查逆转聚体的功能。表达PD突变体VPS35的细胞将被分析是否有生化变化，如线粒体活性和蛋白质分泌的变化。将进行基因阵列分析，以确定基因表达的潜在变化。一种新的帕金森病体外模型的建立将为发现新的分子途径和治疗发展的新途径提供机会。

DESCRIPTION (provided by applicant): This pilot proposal will expand on the recent finding that a dominant mutation in the retromer protein VPS35 causes Parkinson's disease (PD). Retromer proteins are involved in transport of proteins from the endosomes back to the trans-Golgi network. We propose to develop an in vitro model and to perform a series of analyses in order to identify the molecular mechanism(s) by which the mutant form of VPS35 causes PD. To create the model the PD mutant VPS35 protein will be expressed in a cell lines. Analysis will be performed on several levels. We will examine retromer function by analyzing receptor recycling in the cells expressing the PD mutant VPS35. Cells expressing the PD mutant VPS35 will be analyzed for biochemical changes such as changes in mitochondrial activity and protein secretion. Gene array analysis will be performed to identify potential changes in gene expression. The development of a novel in vitro model of PD will provide an opportunity to identify new molecular pathways and new avenues for therapeutic development.