Role of dopamine in alpha-Syn-mediated neurodegeneration

描述（由申请人提供）：由于突触是大脑的功能组成部分，因此特定突触信号/调节的缺陷或丧失是帕金森病（PD）等神经系统疾病的基础。因此，我们的兴趣是了解多巴胺能（DA）神经元和突触选择性变性的细胞和分子机制。在提出的DA细胞死亡的潜在原因中，氧化损伤被认为起重要作用。具有讽刺意味的是，神经递质多巴胺本身可以成为氧化应激的来源，从而有助于PD的选择性DA细胞死亡。本研究旨在揭示多巴胺介导α -突触核蛋白诱导的神经变性的机制。我们将采用分子遗传学，免疫细胞化学和电流测量方法应用于各种转基因果蝇系和原代神经元培养作为模型系统。我们的实验结果将有助于我们理解α -突触核蛋白如何诱导DA稳态破坏，导致细胞质DA水平升高并最终导致特异性神经元死亡的分子机制。在多巴胺调节的基本机制方面，脊椎动物和无脊椎动物之间的高度保守性表明，我们在果蝇身上的研究将对指导合理治疗策略的发展具有重要意义，旨在恢复帕金森病患者被破坏的多巴胺功能/稳态。此外，突触DA释放和细胞质DA浓度的电流记录不仅可以表征DA稳态与特定神经退行性变之间的关系，还可以研究DA介导学习/记忆和药物成瘾的信号机制。

DESCRIPTION (provided by applicant): Since the synapse is a functional building block of the brain, defects in, or loss of, specific synaptic signaling/modulation consequently underlies neurological disorders such as Parkinson's disease (PD). Therefore, our interests are to understand the cellular and molecular mechanisms underlying selective degeneration of dopaminergic (DA) neurons and synapses. Among the proposed underlying causes of DA cell death, oxidative damage is thought to play an important role. Ironically, neurotransmitter dopamine itself can become a source of oxidative stress and consequently contribute to the selective DA cell death in PD. This study aims to reveal mechanisms underlying dopamine's ability to mediate alpha-synuclein-induced neurodegeneration. We will employ molecular genetic, immunocytochemical and amperometrical approaches applied to a variety of transgenic fly lines and primary neuronal cultures as a model system. The results of our experiments will contribute to our understanding of the molecular mechanisms of how alpha-synuclein induces disruption of DA homeostasis, resulting in elevated levels of cytoplasmic DA and eventually leading to specific neuronal death. The high degree of conservation between vertebrates and invertebrates in terms of the basic mechanisms important in DA modulation, suggests that our studies in Drosophila will be important in guiding development of rational treatment strategies aimed at restoring dopamine function/homeostasis that has been disrupted in Parkinson's disease patients. In addition, amperometric recordings of synaptic DA release and cytoplasmic DA concentrations will be very useful not only to characterize the relationship between DA homeostasis and specific neurodegeneration, but also to study DA signaling mechanisms mediating learning/memory and drug addiction.