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

描述(由申请人提供)：有证据表明，线粒体动态特性的异常(分裂、融合、运输、生物发生和有丝分裂)在帕金森病(PD)的神经发病中起着关键作用。这些动态过程对于维持线粒体和线粒体DNA的功能、线粒体到突触的分布、能量产生、细胞死亡机制以及突触的正常发育和功能是必要的。线粒体动力学对神经元尤其重要，而帕金森病中易受伤害的神经元可能尤其依赖于这些过程。遗传和环境毒素相关的帕金森病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线粒体动力学调控的差异，并发现神经元生物能量学的差异可能至少是部分原因，这表明细胞的新陈代谢状态很重要。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变化，我们假设这些变化参与了PD的早期神经病理，因此，可能是神经保护治疗的新靶点。因此，迫切需要了解神经元对线粒体动力学的特异性调节，以及这种调节在帕金森病中是如何改变的。我们提出的研究将扩展我们的初步发现，以更好地描述PD相关遗传和慢性环境模型中神经元线粒体分裂、融合、生物发生和有丝分裂的变化，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，包括在创新的活体脊椎动物PD模型中直接在多巴胺(DA)神经元中对线粒体动力学进行成像和量化，从而更好地剖析线粒体动力学在PD早期神经病理中的作用。这些研究将为神经元对线粒体动力学的调控提供重要信息，并更好地理解线粒体动力学在帕金森病中的综合作用。 公共卫生相关性：这项研究的重点是了解线粒体稳态变化在帕金森氏病神经退行性变中的作用。因为它的目的是阐明早期参与发病机制的潜在潜在机制，它可能确定帕金森病神经保护的新靶点。

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. PUBLIC HEALTH RELEVANCE: This research is focused on understanding the role of changes in mitochondrial homeostasis in the neurodegeneration of Parkinson's disease. Because it is aimed at elucidating potential underlying mechanisms involved early in pathogenesis, it may identify new targets for neuroprotection in Parkinson's disease.