Dys-regulation of Mitochondrial Motility in Parkinsonian Neurodegeneration

项目概述：帕金森病发病机制中的线粒体运动失调我开始研究细胞线粒体运输的调控机制，并将其作为我的长期职业目标。在所有真核细胞中，线粒体都在移动并经历裂变和融合，但需要将线粒体供应到神经元的遥远末端，这使得线粒体在神经元中的运输变得特别紧迫。轴突线粒体运输和分布的错误调节可能是神经变性的关键组成部分。我认为，线粒体的运输对于维持神经元的功能尤其重要，即使它们的运输受到微小的干扰，也可能导致神经退行性疾病。从运动/连接复合体开始，包括运动蛋白-1重链（KHC）， milton和Miro，它们顺行运输轴突线粒体，并阐明了ca++如何通过该复合体调节线粒体运动的机制（Wang和Schwarz， 2009a），我现在想研究该复合体在神经退行性变性中的作用，这是我的直接目标。具体来说，我建议重点关注PINK1和Parkin，它们的突变会导致人类帕金森病。由于这两种蛋白都可以定位于线粒体并进行遗传相互作用，并且PINK1位于线粒体外膜并与KHC/milton/Miro复合物相互作用（Zhou et al., 2008; Weihofen et al., 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，其调控错误可能解释帕金森神经退行性变。因此，我建议研究可能涉及线粒体受损的帕金森病动物模型，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失调与帕金森神经退行性疾病之间的联系，并作为独立的首席研究员继续研究线粒体运动在其他神经退行性疾病中的潜在机制和参与。

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.