Mis-regulation of Mitochondrial Motility in Parkinsonian Neurodegeneration

帕金森神经变性中线粒体运动的错误调节

• 批准号: 8385740
• 负责人: XINNAN WANG
• 金额: $ 24.9万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-01-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8385740
• 关键词: Alleles; Animal Model; Apoptosis; Axon; Axonal Transport; Boston; Cells; Complex; Cues; Defect; Disease; Distal; Drosophila genus; Eukaryotic Cell; Genes; Genetic; Goals; Hippocampus (Brain); Homeostasis; Human; Kinesin; Limb structure; Link; Mammals; Mediating; Mentors; Mitochondria; Modeling; Motor; Movement; Mutate; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Outer Mitochondrial Membrane; PINK1 gene; PTEN gene; Parkin gene; Parkinson Disease; Parkinsonian Disorders; Pathogenesis; Pathway interactions; Pediatric Hospitals; Phase; Phosphorylation; Phosphotransferases; Principal Investigator; Proteins; RNA Interference; Rattus; Reagent; Regulation; career; cell motility; fly; gain of function; loss of function; medical schools; mutant; nervous system disorder; overexpression; parkin gene/protein; trafficking

Project Summary Misregulation of Mitochondrial Motility in Parkinsonian Pathogenesis I set out to understand the regulatory mechanisms underlying mitochondrial transport in cells as my long-term career goal. Mitochondria move and undergo fission and fusion in all eukaryotic cells, but the need to supply mitochondria to the far-flung extremities of neurons creates a particular urgency for mitochondrial transport in neurons. Misregulation of the transport and distribution of mitochondria in axons can be a critical component of neurodegeneration. I propose that the transport of mitochondria is particularly vital for maintaining neuronal function and that even subtle perturbation of their traffic may contribute to neurodegenerative disorders. Starting with a motor/adaptor complex including kinesin-1 heavy chain (KHC), milton and Miro that transports axonal mitochondria anterograde and having elucidated the mechanism how Ca++ regulates mitochondrial motility via this complex (Wang and Schwarz, 2009a), I now would like to investigate the involvement of this complex in neurodegeneration as my immediate goal. Specifically, I propose to focus on PINK1 and Parkin, mutations of which cause Parkinson's disease in humans. Because both proteins can localize to mitochondria and genetically interact, and because PINK1 resides in the outer mitochondrial membrane and interacts with KHC/milton/Miro complex (Zhou et al., 2008; Weihofen et al., 2009), I hypothesize that PINK1 and Parkin also participate in the regulation of mitochondrial transport by regulating KHC/milton/Miro activity, misregulation of which may explain the Parkinsonian neurodegeneration. I therefore propose to look at animal models of Parkinsonism that might involve impaired mitochondria, to determine if mitochondrial transport is abnormal, and to examine the underlying mechanisms. I plan to establish a link between misregulation of mitochondrial motility and Parkinsonian neurodegeneration in my mentored phase here in Children's Hospital Boston and Harvard Medical School, and continue to investigate the underlying mechanisms and the involvement of mitochondrial motility in other neurodegenerative diseases as an independent principal investigator.

项目摘要 帕金森病发病机理中线粒体运动的正调 我着手了解线粒体运输的监管机制 牢房是我的长期职业目标。线粒体移动并进行裂变和融合 所有真核细胞，但需要向遥远的四肢提供线粒体 神经元在神经元中的线粒体转运产生了特殊的紧迫性。 线粒体在轴突中的运输和分布的不正体可能是关键 神经退行性的组成部分。我建议线粒体的运输是 对于维持神经元功能特别重要，甚至微妙的扰动 他们的流量可能导致神经退行性疾病。从A开始 电机/适配器建筑综合体，包括运动蛋白-1重链（KHC），米尔顿和米罗 运输轴突线粒体顺行，并阐明了如何 Ca ++通过这种复合物调节线粒体运动性（Wang and Schwarz，2009a），I 现在想研究这种复合物在神经退行性中的参与 我的直接目标。具体来说，我建议专注于Pink1和Parkin， 引起人类帕金森氏病。因为两种蛋白质都可以定位 线粒体和遗传相互作用，因为pink1位于外部 线粒体膜并与KHC/Milton/Miro综合体相互作用（Zhou等。 2008; Weihofen等，2009），我假设Pink1和Parkin也参与了 通过调节KHC/Milton/Miro活动来调节线粒体运输， 它的正调可能解释了帕金森神经退行性。我因此 建议看可能涉及受损的帕金森主义动物模型 线粒体，确定线粒体转运是否异常，并检查 基本机制。我计划在不利的情况之间建立联系 在我的指导阶段，线粒体运动和帕金森神经退行性的阶段 在波士顿儿童医院和哈佛医学院，并继续调查 基本机制和线粒体运动在其他 神经退行性疾病是独立的主要研究者。