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: 8394930
• 负责人: XINNAN WANG
• 金额: $ 23.8万
• 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/8394930
• 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 帕金森病发病机制中的线粒体运动失调 我开始了解线粒体运输的调节机制， 作为我的长期职业目标。线粒体在细胞中移动， 所有的真核细胞，但需要提供线粒体到遥远的四肢， 神经元中的线粒体转运产生了特别的紧迫性。 轴突中线粒体的运输和分布的失调可能是一个关键因素， 神经退行性变的组成部分。我认为线粒体的运输 对维持神经元功能尤其重要， 它们的运输可能导致神经变性疾病。以开局就是 包括驱动蛋白-1重链（KHC）、米尔顿和Miro的马达/衔接子复合物， 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和施瓦茨，2009 a），I 现在我想研究这种复合物在神经变性中的作用， 我的近期目标具体来说，我建议把重点放在PINK 1和Parkin上， 导致人类帕金森氏症。因为这两种蛋白质都可以定位于 线粒体和基因相互作用，因为PINK 1存在于外部， 线粒体膜并与KHC/米尔顿/Miro复合物相互作用（Zhou et al.， 2008; Weihofen等人，2009年），我假设PINK 1和帕金也参与了 通过调节KHC/米尔顿/Miro活性调节线粒体转运， 这种失调可以解释帕金森神经变性因此我 我建议研究帕金森症的动物模型， 线粒体，以确定线粒体运输是否异常，并检查线粒体的功能。 基本机制。我计划建立一个错误的监管之间的联系， 线粒体运动和帕金森神经退行性疾病的关系 在波士顿儿童医院和哈佛医学院， 线粒体运动的潜在机制和参与其他 神经退行性疾病作为一个独立的主要研究者。