PINK1 Regulation of Neuronal and Mitochondrial Homeostasis

描述(由申请人提供)：PTEN诱导的激酶1(PINK1)突变与常染色体隐性遗传性帕金森综合征有关。早期的研究一致表明PINK1具有神经保护作用，这表明研究这种家族性帕金森病(PD)可能为潜在的治疗策略提供有价值的见解。线粒体调节失调和自噬分别与毒素、遗传和环境方法建立帕金森病模型有关。利用敲除和靶向表达系统，我们鉴定了PINK1下游的一系列线粒体、自噬和轴突稳定功能。利用从对照组和PINK1基因敲除小鼠获得的分化神经细胞系和原代神经元，我们现在将确定PINK1在毒素和遗传性PD模型中的保护机制，重点放在：1)亚细胞定位在PINK1调控线粒体和轴突稳定性中的作用，2)PD连锁突变对调节PINK1神经保护这两个方面的机制的影响，以及3)使用候选和无偏见的蛋白质组方法继续鉴定潜在的PINK1途径介体。实现这个项目的目标是更好地了解PINK1对自噬和线粒体的调控，将为减少帕金森病神经元功能障碍的新治疗策略提供洞察力。

DESCRIPTION (provided by applicant): Mutations in PTEN-induced kinase 1 (PINK1) are associated with autosomal recessive parkinsonism. Early studies have uniformly shown a neuroprotective role for PINK1, indicating that studying this familial form of Parkinson's Disease (PD) may offer valuable insights into potential therapeutic strategies. Dysregulation of mitochondria and autophagy are each centrally implicated in toxin, genetic and environmental approaches to modeling PD. Using knockdown and targeted expression systems, we identified a set of mitochondrial, autophagic and neurite-stabilizing functions downstream of PINK1. Using differentiated neuronal cell lines and primary neurons harvested from control and PINK1 knockout mice, we will now determine mechanisms by which PINK1 protects in toxin and genetic PD models, focusing on: 1) the role of subcellular localization in PINK1 regulation of mitochondrial and neurite stability, 2) the effects of PD-linked mutations on mechanisms that regulate these two facets of PINK1 neuroprotection, and 3) continued characterization of potential PINK1 pathway mediators, using candidate and nonbiased proteomic approaches. Achieving the goals of this project to obtain a better understanding of PINK1 regulation of autophagy and mitochondria will provide insight into new therapeutic strategies to reduce neuronal dysfunction in PD.