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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

基本信息

批准号：
6986044
负责人：
DAEWOO LEE
金额：
$ 16.6万
依托单位：
OHIO UNIVERSITY ATHENS
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-12-01 至 2007-11-30
项目状态：
已结题

项目摘要

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性构建块，因此特定突触信号传导/调节的缺陷或丧失是神经障碍如帕金森病（PD）的基础。因此，我们的兴趣是了解多巴胺能（DA）神经元和突触的选择性变性的细胞和分子机制。在DA细胞死亡的潜在原因中，氧化损伤被认为起着重要作用。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，从而导致PD中的选择性DA细胞死亡。这项研究旨在揭示多巴胺介导α-突触核蛋白诱导的神经退行性变的机制。我们将采用分子遗传学，免疫细胞化学和安培的方法，适用于各种转基因苍蝇线和原代神经元培养作为一个模型系统。我们的实验结果将有助于我们了解α-突触核蛋白如何诱导破坏DA稳态的分子机制，导致细胞质DA水平升高，并最终导致特定的神经元死亡。脊椎动物和无脊椎动物之间的高度保守的DA调制的重要的基本机制，表明我们在果蝇的研究将是重要的指导发展的合理的治疗策略，旨在恢复多巴胺功能/稳态，已被破坏的帕金森病患者。此外，突触DA释放和细胞质DA浓度的安培记录将是非常有用的，不仅要表征DA稳态和特定的神经退行性变之间的关系，而且还研究DA信号转导机制介导的学习/记忆和药物成瘾。