Catechol-induced Inhibition of Alpha-synuclein Fibrils

描述（由申请人提供）：α -突触核蛋白的聚集/纤颤是帕金森病（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复制与罕见的家族性PD病例有关。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 -突触核蛋白原纤维。目前迫切需要一种有效的治疗帕金森病的方法，因为目前的治疗方法对治疗症状只有部分有效。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 -突触核蛋白纤维的纤颤和分解现有纤维的潜力。

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.