Catechol-induced Inhibition of Alpha-synuclein Fibrils

儿茶酚诱导的α-突触核蛋白原纤维的抑制

• 批准号: 6966954
• 负责人: ANTHONY L FINK
• 金额: $ 28万
• 依托单位: UNIVERSITY OF CALIFORNIA SANTA CRUZ
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6966954
• 关键词: Lewy body; Parkinson' s disease; alpha synuclein; catechols; flavonoids; high performance liquid chromatography; inhibitor /antagonist; mass spectrometry; neural degeneration

DESCRIPTION (provided by applicant): The aggregation/fibrillation of alpha-synuclein is a critical factor in Parkinson's disease (PD). Alpha-Synuclein is a significant component of intracellular inclusions known as Lewy bodies that are the pathological hallmark of PD and mutations and gene triplication of alpha-synuclein have been associated with rare cases of familial PD. Our overall goals are to design molecules that will inhibit alpha-synuclein aggregation, and disaggregate existing alpha-synuclein fibrils. There is a critical need for an effective treatment of Parkinson's disease, since current therapies are only partially effective in treating the symptoms. Our preliminary data indicate that some catechols, flavonoids and related compounds have the potential to inhibit fibrillation of alpha-synuclein and disaggregate existing fibrils. The aims of this proposal are: 1) To determine the underlying molecular mechanisms of the inhibition of alpha-synuclein fibrillation by catechols, flavonoids and related compounds. Our preliminary investigations suggest that it is an oxidized form of the catechol that is most effective in inhibiting fibrillation. 2) To identify the active species, and the mechanism of disaggregation of alpha-synuclein fibrils by catechol-type compounds. 3) To determine whether catechols and related compounds prevent alpha-synuclein fibrillation and disaggregate fibrils in vivo. We will also perform a systematic investigation of the most promising compounds (as inhibitors and "disaggregators") to identify key structural features in order to identify additional molecules that might be more suited for potential therapeutic uses. The results of the proposed research should 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.

描述（由申请方提供）：α-突触核蛋白的聚集/纤维化是帕金森病（PD）的关键因素。α-突触核蛋白是称为路易体的细胞内包涵体的重要组分，路易体是PD的病理标志，并且α-突触核蛋白的突变和基因三倍化与罕见的家族性PD病例相关。我们的总体目标是设计抑制α-突触核蛋白聚集的分子，并解聚现有的α-突触核蛋白原纤维。迫切需要有效治疗帕金森病，因为目前的疗法在治疗症状方面仅部分有效。我们的初步数据表明，一些儿茶酚，类黄酮和相关化合物有可能抑制α-突触核蛋白的原纤维化和解聚现有的原纤维。 本研究的目的是：1）确定儿茶酚类、黄酮类及相关化合物抑制α-突触核蛋白纤维化的潜在分子机制。我们的初步研究表明，它是一种氧化形式的儿茶酚，是最有效的抑制纤维化。2)确定儿茶酚类化合物对α-突触核蛋白原纤维解聚的活性物质和机制。3)确定儿茶酚和相关化合物是否能在体内防止α-突触核蛋白纤维化和解聚纤维。我们还将对最有前途的化合物（作为抑制剂和“解聚剂”）进行系统研究，以确定关键的结构特征，从而确定可能更适合潜在治疗用途的其他分子。 拟议的研究结果应该为α-突触核蛋白聚集的抑制剂提供线索，并为潜在的治疗方法奠定基础。从长远来看，这项研究可以为帕金森病的治疗提供新的策略。