Catechol-induced Inhibition of Alpha-synuclein Fibrils

描述（由申请人提供）：α-突触核蛋白的聚集/纤维化是帕金森病（PD）的关键因素。 α-突触核蛋白是被称为路易体的细胞内包涵体的重要组成部分，路易体是 PD 的病理标志，α-突触核蛋白的突变和基因三倍体与罕见的家族性 PD 病例有关。我们的总体目标是设计能够抑制 α-突触核蛋白聚集并分解现有 α-突触核蛋白原纤维的分子。迫切需要有效治疗帕金森病，因为目前的疗法对治疗症状仅部分有效。我们的初步数据表明，一些儿茶酚、类黄酮和相关化合物具有抑制 α-突触核蛋白原纤维化和分解现有原纤维的潜力。 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-突触核蛋白纤维颤动的潜在分子机制。我们的初步研究表明，它是儿茶酚的氧化形式，对抑制纤维性颤动最有效。 2) 鉴定活性物质，以及儿茶酚类化合物解聚α-突触核蛋白原纤维的机制。 3) 确定儿茶酚和相关化合物是否可以预防α-突触核蛋白原纤维化并在体内分解原纤维。我们还将对最有前途的化合物（作为抑制剂和“分解剂”）进行系统研究，以确定关键的结构特征，从而识别可能更适合潜在治疗用途的其他分子。 拟议研究的结果应该为α-突触核蛋白聚集抑制剂提供线索，并为潜在的治疗方法奠定基础。从长远来看，这项研究可以为治疗帕金森病提供新策略。

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.