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.

项目概要 帕金森病发病机制中线粒体运动的失调 我开始了解线粒体运输的调控机制 细胞作为我长期的职业目标。线粒体移动并进行裂变和融合 所有真核细胞，但需要向远处的四肢提供线粒体 神经元对神经元中的线粒体运输产生了特殊的紧迫性。 轴突中线粒体运输和分布的失调可能是一个关键 神经变性的组成部分。我认为线粒体的运输是 对于维持神经元功能尤其重要，即使是细微的扰动 它们的交通可能会导致神经退行性疾病。从一个开始 马达/适配器复合体，包括驱动蛋白-1 重链 (KHC)、milton 和 Miro 顺行运输轴突线粒体并阐明了其机制 Ca++ 通过该复合物调节线粒体运动（Wang 和 Schwarz，2009a），I 现在想研究这种复合物与神经退行性变的关系 我的近期目标。具体来说，我建议重点关注 PINK1 和 Parkin，它们的突变 导致人类帕金森病。因为这两种蛋白质都可以定位于 线粒体和基因相互作用，并且由于 PINK1 位于外层 线粒体膜并与 KHC/milton/Miro 复合物相互作用（Zhou 等人， 2008年； Weihofen et al., 2009），我假设 PINK1 和 Parkin 也参与了 通过调节 KHC/milton/Miro 活性来调节线粒体运输， 其调节不当可以解释帕金森神经变性。我因此 建议研究可能涉及受损的帕金森病动物模型 线粒体，以确定线粒体运输是否异常，并检查 底层机制。我计划在监管不当之间建立联系 线粒体运动和帕金森神经变性在我的指导阶段在这里 在波士顿儿童医院和哈佛医学院继续调查 线粒体运动的潜在机制和参与其他 作为独立首席研究员的神经退行性疾病。