Models of Familial Parkinson's Disease: PINK1

描述（由申请人提供）：PINK 1基因突变是常染色体隐性遗传性帕金森病（PD）的罕见遗传原因。PINK 1蛋白在已鉴定突变的家族中不存在或似乎功能上无活性。因此，PINK 1基因突变可能通过功能丧失导致PD。目前很难完全理解PINK 1基因突变是如何导致PD的，因为它的功能在很大程度上是未知的。PINK 1被鉴定为线粒体富集蛋白激酶。PINK 1功能的丧失增加了细胞对氧化应激的易感性。P1 NK 1功能的丧失如何导致DA神经元的丧失和PD有待进一步研究。我们建议产生和表征PINK 1基因敲除小鼠，以正式测试PINK 1功能缺失是PINK 1突变导致PD的原因这一假设。因此，提出了进一步表征PINK 1在PD发病机制中的作用的实验。在具体目标#1中，我们将开发和表征PINK 1敲除小鼠。在具体目标#2中，我们将评估PINK 1敲除对环境毒素的敏感性，包括MPTP诱导的多巴胺能细胞死亡。在特定目标#3中，我们将通过将PINK 1敲除与Parkin和DJ-1敲除交叉来确定PINK 1、Parkin和/或DJ-1是否参与共同的致病途径。开发和表征PINK 1敲除，了解PINK 1和线粒体功能在PD发病机制中的关系，可以深入了解这些基因产物诱导神经元损伤的分子机制，并可能提供新的治疗方法和靶点，以防止这种家族相关基因在PD退行性过程中的毒性作用。

DESCRIPTION (provided by applicant): Mutations in the PINK1 gene are a rare genetic cause of autosomal recessive Parkinson's disease (PD). The PINK1 protein is either absent or appears to be functionally inactive in the families in which the mutations have been identified. Thus, mutations in the PINK1 gene probably cause PD through a loss of function. It is difficult at this juncture to fully appreciate how mutations in the PINK1 gene cause PD, as its function is largely unknown. PINK1 was identified as a mitochondrial enriched protein kinase. Loss of function of PINK1 increases cellular susceptibility to oxidative stress. How a loss of function of P1NK1 leads to loss of DA neurons and PD awaits further study. We propose to generate and characterize PINK1 knockout mice to formally test the hypothesis that the absence of PINK1 function is the cause of PD due to PINK1 mutations. Accordingly experiments are proposed to further characterize the role of PINK1 in the pathogenesis of PD. In Specific Aim #1 we will develop and characterize PINK1 knockout mice. In Specific Aim #2 we will we will evaluate the sensitivity of PINK1 knockouts to environmental toxins including MPTP-induced dopaminergic cell death. In Specific Aim #3 we will determine whether PINK1, Parkin and/or DJ-1 participate in a common pathogenic pathway by crossing PINK1 knockouts with Parkin and DJ-1 knockouts. Development and characterization of PINK1 knockouts, understanding the relationship of PINK1 and mitochondrial function in the pathogenesis of PD may provide insight into the molecular mechanisms by which these gene products induce neuronal damage and may provide novel therapeutics and targets to prevent the toxic effects of this familial associated gene in the degenerative process of PD.