Dept. of Physiology & Biochemistry, University of Malta, Msida MSD 2080, Malta.
FEBS Lett. 2011 Apr 20;585(8):1113-20. doi: 10.1016/j.febslet.2011.03.046. Epub 2011 Mar 31.
Aggregation of alpha-synuclein (αS) into oligomers is critically involved in the pathogenesis of Parkinson's disease (PD). Using confocal single-molecule fluorescence spectroscopy, we have studied the effects of 14 naturally-occurring polyphenolic compounds and black tea extract on αS oligomer formation. We found that a selected group of polyphenols exhibited potent dose-dependent inhibitory activity on αS aggregation. Moreover, they were also capable of robustly disaggregating pre-formed αS oligomers. Based upon structure-activity analysis, we propose that the key molecular scaffold most effective in inhibiting and destabilizing self-assembly by αS requires: (i) aromatic elements for binding to the αS monomer/oligomer and (ii) vicinal hydroxyl groups present on a single phenyl ring. These findings may guide the design of novel therapeutic drugs in PD.
α-突触核蛋白（αS）的聚集在帕金森病（PD）的发病机制中起着关键作用。使用共聚焦单分子荧光光谱法，我们研究了 14 种天然多酚化合物和红茶提取物对αS 寡聚体形成的影响。我们发现，一组选定的多酚对αS 聚集表现出强烈的剂量依赖性抑制活性。此外，它们还能够有效地解聚预先形成的αS 寡聚物。基于结构-活性分析，我们提出最有效地抑制和破坏αS 自组装的关键分子支架需要：（i）用于与αS 单体/寡聚物结合的芳族元素，和（ii）单苯环上存在的相邻羟基。这些发现可能为 PD 的新型治疗药物设计提供指导。
