Institute of Physical Biology, Heinrich-Heine-University, 40225 Düsseldorf, Germany.
Department of Hematology, Oncology and Clinical Immunology, Heinrich-Heine-University,40225 Düsseldorf, Germany.
Int J Mol Sci. 2020 Mar 14;21(6):1995. doi: 10.3390/ijms21061995.
The amyloid fibril formation by α -synuclein is a hallmark of various neurodegenerative disorders, most notably Parkinson's disease. Epigallocatechin gallate (EGCG) has been reported to be an efficient inhibitor of amyloid formation by numerous proteins, among them α -synuclein. Here, we show that this applies only to a small region of the relevant parameter space, in particular to solution conditions where EGCG readily oxidizes, and we find that the oxidation product is a much more potent inhibitor compared to the unmodified EGCG. In addition to its inhibitory effects, EGCG and its oxidation products can under some conditions even accelerate α -synuclein amyloid fibril formation through facilitating its heterogeneous primary nucleation. Furthermore, we show through quantitative seeding experiments that, contrary to previous reports, EGCG is not able to re-model α -synuclein amyloid fibrils into seeding-incompetent structures. Taken together, our results paint a complex picture of EGCG as a compound that can under some conditions inhibit the amyloid fibril formation of α -synuclein, but the inhibitory action is not robust against various physiologically relevant changes in experimental conditions. Our results are important for the development of strategies to identify and characterize promising amyloid inhibitors.
α -突触核蛋白的淀粉样纤维形成是各种神经退行性疾病的标志，尤其是帕金森病。表没食子儿茶素没食子酸酯（EGCG）已被报道为许多蛋白质（包括α -突触核蛋白）形成淀粉样纤维的有效抑制剂。在这里，我们表明这仅适用于相关参数空间的一小部分区域，特别是在 EGCG 容易氧化的溶液条件下，并且我们发现氧化产物比未修饰的 EGCG 具有更强的抑制作用。除了抑制作用外，EGCG 和其氧化产物在某些条件下甚至可以通过促进其异质初级成核来加速α -突触核蛋白淀粉样纤维的形成。此外，我们通过定量接种实验表明，与之前的报告相反，EGCG 不能将α -突触核蛋白淀粉样纤维重塑成无接种能力的结构。总之，我们的结果描绘了 EGCG 作为一种化合物的复杂情况，在某些条件下可以抑制α -突触核蛋白的淀粉样纤维形成，但抑制作用在实验条件下的各种生理相关变化下并不稳健。我们的结果对于开发识别和表征有前途的淀粉样抑制剂的策略非常重要。
