Dys-regulation of Mitochondrial Motility in Parkinsonian Neurodegeneration

描述(申请人提供)：项目摘要：帕金森病发病机制中线粒体运动的错误调节我开始了解细胞中线粒体运输的调节机制，作为我的长期职业目标。线粒体在所有真核细胞中运动并经历分裂和融合，但向神经元遥远的末端供应线粒体的需要为线粒体在神经元中的运输创造了特别的紧迫性。轴突中线粒体运输和分布的失调可能是神经退行性变的关键组成部分。我认为线粒体的运输对维持神经元的功能特别重要，即使线粒体运输的细微干扰也可能导致神经退行性疾病。从运动素-1重链(kinesin-1 Heavy Chain，KHC)、米尔顿(Milton)和米罗(Miro)等运动/适配器复合体开始，阐明了钙离子如何通过这个复合体调节线粒体运动的机制(Wang和Schwarz，2009a)，现在我想研究这个复合体在神经退行性变中的作用作为我的直接目标。具体地说，我建议将重点放在PINK1和Parkin上，它们的突变会导致人类患上帕金森氏症。由于这两种蛋白都可以定位于线粒体并在基因上相互作用，并且由于PINK1位于线粒体外膜并与KHC/Milton/Miro复合体相互作用(周等人，2008；Wehofen等人，2009)，我假设PINK1和Parkin也通过调节KHC/Milton/Miro活性参与线粒体运输的调节，这可能是帕金森病神经变性的原因。因此，我建议研究可能涉及线粒体受损的帕金森氏症动物模型，以确定线粒体运输是否异常，并检查潜在的机制。我计划在我在波士顿儿童医院和哈佛医学院的指导阶段建立线粒体运动性错误与帕金森神经变性之间的联系，并作为独立的首席研究员继续研究线粒体运动性在其他神经退行性疾病中的潜在机制和参与。 公共卫生相关性：帕金森氏病是最常见的神经系统疾病之一，虽然已经确定了几个致病基因，但确切的发病机制尚不清楚。强有力的证据表明线粒体在帕金森病中存在异常，因此我想进一步研究线粒体运动性在帕金森神经退行性变中的作用，这将为更好地了解细胞缺陷和治疗提供线索。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Parkinson's disease is one of the most common neurological disorders, and although several disease-causing genes have been identified, the exact pathogenesis is unknown. Robust evidence has suggested mitochondrial abnormalities in the disease, therefore I would like to further investigate the involvement of mitochondrial motility in Parkinsonian neurodegeneration, which will provide a better understanding of the cellular defects and promising cues for therapies.