Neuronal regulation of mitochondrial dynamics in models of Parkinson's disease.

描述（由申请人提供）：证据表明，线粒体动态特性（分裂、融合、转运、生物发生和线粒体自噬）异常在帕金森病（PD）神经发病机制中起关键作用。这些动态过程对于功能性线粒体和线粒体DNA的维持、线粒体向突触的分布、能量产生、细胞死亡机制以及适当的突触发育和功能是必需的。线粒体动力学对神经元特别重要，PD中脆弱的神经元可能特别依赖于这些过程。遗传和环境毒素相关的PD模型都与线粒体动力学失调有关，但对神经元中的这些过程知之甚少。 我们和其他人发现了神经元中线粒体动力学调节的差异，并发现神经元生物能量学的差异可能至少部分负责，这表明细胞的代谢状态很重要。此外，我们在慢性神经毒性PD相关模型中发现了神经元线粒体动力学的早期改变，我们假设这些变化与PD的早期神经病理学有关，因此是神经保护治疗的潜在新靶点。因此，迫切需要了解线粒体动力学的神经元特异性调节以及这种调节在PD中是如何改变的。我们提出的研究，将扩大我们的初步研究结果，以更好地表征神经元线粒体分裂，融合，生物发生和线粒体自噬在PD相关的遗传和慢性环境模型的改变，并开始阐明可能的机制。重要的是，我们还将扩大我们的工作，包括直接在多巴胺（DA）神经元中，在一个创新的活脊椎动物PD模型中对线粒体动力学进行成像和定量，从而更好地剖析线粒体动力学在PD早期神经病理学中的作用。这些研究将提供重要的信息，神经元调节线粒体动力学，以及提供一个更好的理解线粒体动力学在PD中的综合作用。

DESCRIPTION (provided by applicant): Evidence suggests that abnormalities in dynamic properties of mitochondria (fission, fusion, transport, biogenesis, and mitophagy) play a critical role in Parkinson's disease (PD) neuropathogenesis. These dynamic processes are necessary for maintenance of functional mitochondria and mitochondrial DNA, distribution of mitochondria to synapses, energy production, cell death mechanisms, and proper synaptic development and function. Mitochondrial dynamics are particularly critical to neurons, and the vulnerable neurons in PD may be especially dependent on these processes. Both genetic and environmental toxin-related models of PD have been linked to dysregulation of mitochondrial dynamics, but less is known about these processes in neurons. We and others have found differences in regulation of mitochondrial dynamics in neurons and have found that differences in neuronal bioenergetics may at least in part be responsible, suggesting the metabolic state of the cell is important. In addition, we found early alterations in mitochondrial dynamics in neurons in a chronic neurotoxic PD-relevant model, and we hypothesize that these changes are involved in early neuropathology in PD, and thus, are potential new targets for neuroprotective therapies. Thus, there is a critical need to understand neuron-specific regulation of mitochondrial dynamics and how this is altered in PD. We propose studies that will expand on our initial findings to better characterize alterations in neuronal mitochondrial fission, fusion, biogenesis and mitophagy in both PD-relevant genetic and chronic environmental models, and begin to elucidate possible mechanisms. Importantly, we will also expand our work to include imaging and quantification of mitochondrial dynamics directly, in dopamine (DA) neurons, in an innovative, living vertebrate PD model, thus better dissecting the role of mitochondrial dynamics in early neuropathology in PD. These studies will provide important information on neuronal regulation of mitochondrial dynamics, as well as provide a better understanding of the integrated role of mitochondrial dynamics in PD.