PINK1 Regulation of Neuronal and Mitochondrial Homeostasis

PINK1 对神经元和线粒体稳态的调节

• 批准号: 8181791
• 负责人: Charleen T Chu
• 金额: $ 33.14万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-15 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8181791
• 关键词: Affect; Autophagocytosis; Cell Line; Cells; Cellular biology; Data; Disease; Disease model; Genetic; Goals; Harvest; Homeostasis; Human; Immunochemistry; In Vitro; Injury; Intoxication; Knock-in Mouse; Knockout Mice; Knowledge; Light; Link; MAP1 Microtubule-Associated Protein; Mass Spectrum Analysis; Mediating; Mediator of activation protein; Mitochondria; Modeling; Morphology; Mus; Mutation; Nerve Degeneration; Neurites; Neurodegenerative Disorders; Neuronal Dysfunction; Neuronal Injury; Neurons; Organelles; PTEN gene; Parkinson Disease; Parkinsonian Disorders; Pathway interactions; Phosphorylation; Phosphorylation Site; Phosphotransferases; Process; Proteins; Proteomics; Recessive Parkinsonism, Autosomal; Recombinants; Regulation; Role; Signal Pathway; Site; Stress; Synapses; System; Testing; Therapeutic; Toxin; brain tissue; in vivo; insight; leucine-rich repeat kinase 2; loss of function mutation; mitochondrial autophagy; mitochondrial dysfunction; mutant; neuroprotection; novel; novel therapeutics; overexpression; prevent; therapeutic target

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. PUBLIC HEALTH RELEVANCE: Loss-of-function mutations in PTEN-induced kinase 1 (PINK1) contribute to a recessive form of Parkinson's disease. Completion of this study will enhance understanding of mechanisms by which PINK1 confers protection in models of parkinsonian injury, and the subcellular regulation of its functions. Developing this basic knowledge represents a necessary first step towards continued identification of potential therapeutic targets to prevent or slow neurodegeneration in Parkinson's and related diseases.

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病相关。早期研究一致显示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。线粒体和自噬的失调都与毒素、遗传和环境方法有关。通过敲低和靶向表达系统，我们鉴定了PINK1下游的一组线粒体、自噬和神经突稳定功能。利用从对照小鼠和PINK1敲除小鼠中获得的分化的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相关突变对调节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学方法继续表征潜在的PINK1途径介质。实现本项目的目标，更好地了解PINK1对自噬和线粒体的调控，将为减少PD的神经元功能障碍提供新的治疗策略。