Role of dopamine in alpha-Syn-mediated neurodegeneration

多巴胺在 α-Syn 介导的神经变性中的作用

• 批准号: 6853061
• 负责人: DAEWOO LEE
• 金额: $ 17万
• 依托单位: OHIO UNIVERSITY ATHENS
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-12-01 至 2006-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6853061
• 关键词: Drosophilidae; Parkinson' s disease; alpha synuclein; biological signal transduction; cell death; dopamine; electrophysiology; embryo /fetus tissue /cell culture; genetically modified animals; green fluorescent proteins; homeostasis; immunocytochemistry; molecular genetics; neural degeneration; neurons; neurotransmitter transport; oxidative stress; synapses

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.

描述（由申请人提供）：由于突触是大脑的功能构件，因此特定突触信号传导/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。在所提出的 DA 细胞死亡的根本原因中，氧化损伤被认为发挥着重要作用。讽刺的是，神经递质多巴胺本身可以成为氧化应激的来源，从而导致 PD 中 DA 细胞的选择性死亡。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能力的机制。我们将采用分子遗传学、免疫细胞化学和电流分析方法应用于各种转基因蝇系和原代神经元培养物作为模型系统。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定神经元死亡的分子机制。脊椎动物和无脊椎动物之间在 DA 调节中重要的基本机制方面具有高度的保守性，这表明我们对果蝇的研究对于指导制定合理的治疗策略非常重要，该策略旨在恢复帕金森病患者中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对于表征 DA 稳态和特定神经退行性变之间的关系非常有用，而且对于研究介导学习/记忆和药物成瘾的 DA 信号传导机制也非常有用。