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: 7367908
• 负责人: GLENN L MILLHAUSER
• 金额: $ 28.28万
• 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 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7367908
• 关键词: Animal Model; Catechols; Cells; Classification; Data; Deposition; Development; Flavonoids; Gene Mutation; Goals; In Vitro; Investigation; Lead; Lewy Bodies; Modification; Molecular; Molecular Structure; Mutation; Neurodegenerative Disorders; Parkinson Disease; Pathway interactions; Process; Protein Overexpression; Proteins; Reporting; Research; Role; Running; Symptoms; Testing; Therapeutic; Therapeutic Uses; Work; alpha synuclein; analog; base; cytotoxic; design; in vivo; inhibitor/antagonist; interest; neurotoxic; oxidation; prevent; research study; synuclein

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（由申请人提供）：α-突触核蛋白的聚集/纤颤是帕金森氏病（PD）的关键因素。 α-突触核蛋白是细胞内夹杂物的重要组成部分，称为Lewy体，是PD的病理标志，突变和α-突触核蛋白的基因三分一式化与罕见的家族性PD相关。我们的总体目标是设计将抑制α-核蛋白聚集的分子，并分解现有的α-核蛋白原纤维。迫切需要有效治疗帕金森氏病，因为当前的疗法仅在治疗症状方面有效。我们的初步数据表明，某些儿茶酚，类黄酮和相关化合物具有抑制α-突触核蛋白的纤颤并分解现有的原纤维的原纤维。 该提案的目的是：1）确定儿茶酚，类黄酮和相关化合物抑制α-突触核蛋白纤维纤维的潜在分子机制。我们的初步研究表明，在抑制纤颤中最有效的儿茶酚的一种氧化形式。 2）鉴定活性物质以及通过儿茶醇型化合物对α-突触核蛋白原纤维分解的机理。 3）确定儿茶酚和相关化合物是否可以防止α-突触核蛋白的纤颤并在体内分解原纤维。我们还将对最有希望的化合物（作为抑制剂和“分类器”）进行系统研究，以识别关键的结构特征，以识别可能更适合潜在治疗用途的其他分子。 拟议研究的结果应为α-突触核蛋白聚集的抑制剂提供潜在客户，并为潜在的治疗方法奠定基础。从长远来看，这项研究可以为治疗帕金森氏病提供新的策略。