Mis-regulation of Mitochondrial Motility in Parkinsonian Neurodegeneration

项目摘要 帕金森病发病机制中线粒体运动的失调 我开始了解线粒体转运背后的调控机制 细胞是我长期的职业目标。线粒体在体内移动并经历分裂和融合 所有的真核细胞，但需要提供线粒体到遥远的 神经元为线粒体在神经元中的运输创造了特殊的紧迫感。 轴突中线粒体的运输和分布的错误调节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是 对于维持神经元功能尤其重要，即使是微妙的扰动 它们的流量可能会导致神经退行性疾病。以一个 包括动蛋白-1重链(KHC)、米尔顿和米罗在内的马达/适配器复合体 轴突线粒体顺行运输及其机制 Ca++通过这种复合体调节线粒体的运动(Wang和Schwarz，2009a)，即 现在想要调查这个复合体在神经退行性变中的参与 我的近期目标是。具体地说，我建议关注PINK1和Parkin，即PINK1和Parkin的突变 会导致人类患上帕金森氏症。因为这两种蛋白质都可以定位到 线粒体和基因相互作用，因为PINK1驻留在外部 线粒体膜并与KHC/Milton/Miro复合体相互作用(周等， 2008年；Wehofen等人，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， 这可能是帕金森氏症神经退行性变的原因。因此，我 建议研究帕金森症的动物模型，这些动物模型可能涉及受损 以确定线粒体转运是否异常，并检查 潜在的机制。我计划建立一个联系，在监管不善和 在我的指导阶段，线粒体运动和帕金森神经变性 在波士顿儿童医院和哈佛医学院，并继续调查 线粒体运动的潜在机制及其在其他疾病中的作用 神经退行性疾病作为独立的首席研究员。

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.