PINK1 Regulation of Neuronal and Mitochondrial Homeostasis

PINK1 对神经元和线粒体稳态的调节

• 批准号: 8697145
• 负责人: Charleen T Chu
• 金额: $ 32.81万
• 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 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8697145
• 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.

描述（由申请人提供）：PTEN诱导的激酶1（pink1）中的突变与常染色体隐性帕金森主义有关。早期研究已统一地显示了PINK1的神经保护作用，表明研究这种家族形式的帕金森氏病（PD）可能会为潜在的治疗策略提供宝贵的见解。线粒体和自噬的失调均与毒素，遗传和环境方法进行建模PD有关。使用敲低和靶向表达系统，我们确定了一组PINK1下游的线粒体，自噬和神经突稳定功能。使用从对照和Pink1敲除小鼠收集的区分神经元细胞系和原发性神经元，我们现在将确定PINK1在毒素和遗传PD模型中保护粉红色的机制，重点是：1）粉红色的1）粉红色的线粒体和神经脉络性粉红色粉红色粉红色的效果的粉红色粉红色调节的作用，2） 3）使用候选和无偏蛋白质组学方法的潜在PINK1途径介体的持续表征。实现该项目的目标，以更好地了解自动噬和线粒体的PINK1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。

项目成果

PKA Phosphorylation of NCLX Reverses Mitochondrial Calcium Overload and Depolarization, Promoting Survival of PINK1-Deficient Dopaminergic Neurons.

• DOI: 10.1016/j.celrep.2015.08.079
• 发表时间: 2015-10-13
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Kostic M;Ludtmann MH;Bading H;Hershfinkel M;Steer E;Chu CT;Abramov AY;Sekler I
• 通讯作者: Sekler I