PINK1 Regulation of Neuronal and Mitochondrial Homeostasis

描述（由申请方提供）：PTEN诱导的激酶1（PINK1）突变与常染色体隐性帕金森综合征相关。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。线粒体和自噬的调节异常分别与建模PD的毒素、遗传和环境方法密切相关。使用敲除和靶向表达系统，我们确定了一组线粒体，自噬和神经突稳定功能下游的PINK1。使用从对照和PINK1敲除小鼠中收获的分化的神经元细胞系和原代神经元，我们现在将确定PINK1在毒素和遗传PD模型中的保护机制，重点是：1）亚细胞定位在PINK1调节线粒体和神经突稳定性中的作用，2）PD连锁突变对调节PINK1神经保护的这两个方面的机制的影响，和3）继续表征潜在的PINK1通路介质，使用候选和无偏见的蛋白质组学方法。实现该项目的目标，以更好地了解PINK1对自噬和线粒体的调节，将为减少PD中神经元功能障碍的新治疗策略提供见解。

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.