The Role of Dopamine and its Analogs in the inhibition*

描述(由申请人提供) α-突触核蛋白的聚集被认为是导致 帕金森病(PD)的病因学。α-突触核蛋白是 路易小体和路易神经突起，细胞内的包涵体是一种 帕金森氏症的病理特征。迫切需要一种 帕金森氏症的有效治疗，因为目前的治疗方法 在治疗症状方面部分有效。通过建议的研究，我们 计划开发α-突触核蛋白纤颤抑制剂，这可能导致 阻止疾病进展的新疗法。我们最近发现， 多巴胺和几个相关分子不仅抑制 α-突触核蛋白纤维在体外，但也分解现有的α-突触核蛋白 纤维在体外形成。这一意想不到的观察引发了几个显而易见的 问题，包括：L-多巴或多巴胺产量的减少 水平是帕金森病的触发因素吗？多巴胺及其类似物会溶解吗？ 路易身体？我们能不能找到相关的化合物来构成 治疗性干预？多巴胺抑制脑出血的机制是什么？ α-突触核蛋白纤颤？我们在这项建议中的目标是：(1)测试 假设多巴胺及其类似物与一种 α-突触核蛋白纤颤的中间体，从而抑制原纤维的形成， 并确切地研究多巴胺和相关化合物如何防止纤维 队形。了解DA如何阻止α-突触核蛋白的纤颤应该 为设计具有潜在拖累作用的抑制剂提供基础 防止α-突触核蛋白纤颤。(2)确定DA及其类似物是否 还可以使用组织切片和动物在体内防止纤维形成 模特们。(3)确定多巴胺结构的基本成分 抑制α-突触核蛋白纤颤，并设计新的抑制 基于这一知识的A-突触核蛋白聚集。建议的研究结果 研究将为α-突触核蛋白聚集的抑制剂和 为潜在的治疗方法奠定基础。从长远来看，这是 研究可能会为帕金森氏症的治疗提供新的策略。

DESCRIPTION (provided by applicant) The aggregation of alpha-synuclein is believed to be a critical factor in the etiology of Parkinson's disease (PD). alpha-Synuclein is the major component of Lewy bodies and Lewy neurites, the intracellular inclusions that are a pathological hallmark of Parkinson's disease. There is a critical need for an effective treatment of Parkinson's disease, since current therapies are only partially effective in treating the symptoms. Through the proposed research we plan to develop inhibitors of alpha-Synuclein fibrillation, which could lead to new therapies to halt the disease progression. We recently discovered that dopamine and several related molecules not only inhibit the formation of alpha-Synuclein fibrils in vitro, but also break down existing a-synuclein fibrils formed in vitro. This unexpected observation raises several obvious questions, including: Could a decrease in L-DOPA or dopamine production or levels be a triggering factor in PD? Will dopamine and its analogs dissolve Lewy bodies? Can we find related compounds that would form the basis of a therapeutic intervention? What is the mechanism of dopamine inhibition of alpha-Synuclein fibrillation? Our goals in this proposal are: (1) To test the hypothesis that dopamine and its analogs bind specifically and tightly to an intermediate of alpha-Synuclein fibrillation, thus inhibiting fibril formation, and to investigate exactly how dopamine and related compounds prevent fibril formation. Knowing how DA prevents fibrillation of alpha-Synuclein should provide the basis for the design of inhibitors that will be potential drags for preventing alpha-synuclein fibrillation. (2) To determine if DA and its analogs also prevent fibril formation in vivo using both tissue sections and animal models. (3) To determine the essential parts of the dopamine structure for inhibition of alpha-Synuclein fibrillation, and to design new inhibitors of a-synuclein aggregation based on this knowledge. The results of the proposed research will provide leads for inhibitors of alpha-synuclein aggregation and lay the groundwork for potential therapeutic approaches. In the long-run this research could provide new strategies for the treatment of Parkinson's disease.