Catechol-induced Inhibition of Alpha-synuclein Fibrils

描述(申请人提供)：α-突触核蛋白的聚集/纤颤是帕金森病(PD)的关键因素。α-突触核蛋白是细胞内包涵体的重要组成部分，被称为路易小体，是帕金森病的病理标志，α-突触核蛋白的突变和基因三倍体与罕见的家族性帕金森病有关。我们的总体目标是设计抑制α-突触核蛋白聚集的分子，并分解现有的α-突触核蛋白纤维。帕金森氏症的有效治疗是迫切需要的，因为目前的治疗方法在治疗症状方面只有部分有效。我们的初步数据表明，一些儿茶酚、类黄酮类和相关化合物有可能抑制α-突触核蛋白的纤颤，并解聚现有的纤维。 这项建议的目的是：1)确定儿茶酚、类黄酮及相关化合物抑制α-突触核蛋白纤颤的潜在分子机制。我们的初步研究表明，它是儿茶酚的一种氧化形式，在抑制纤颤方面最有效。2)鉴定儿茶酚型化合物解聚α-突触核蛋白纤维的活性物种和机理。3)确定儿茶酚及其相关化合物在体内是否能阻止α-突触核蛋白纤颤和解聚纤维。我们还将对最有希望的化合物(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，以便确定更多可能更适合潜在治疗用途的分子。 拟议的研究结果应该会为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，这项研究可能会为帕金森氏症的治疗提供新的策略。

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.