Department of Physics, State Key Laboratory of Surface Physics, Key Laboratory for Computational Physical Sciences (Ministry of Education), Fudan University, Shanghai 200438, People's Republic of China.
Department of Physics, State Key Laboratory of Surface Physics, Key Laboratory for Computational Physical Sciences (Ministry of Education), Fudan University, Shanghai 200438, People's Republic of China.
Int J Biol Macromol. 2022 Nov 1;220:316-325. doi: 10.1016/j.ijbiomac.2022.08.088. Epub 2022 Aug 18.
Parkinson's disease (PD) is the second most common neurodegenerative diseases with no cure yet and its major hallmark is α-synuclein fibrillary aggregates. The crucial role of α-synuclein aggregation in PD makes it an attractive target for potential disease-modifying therapies. Disaggregation of α-synuclein fibrils is considered as one of the promising therapeutic strategies to treat PD. The wild type (WT) and mutant α-synuclein fibrils exhibit different polymorphs and provide therapeutic targets for PD. Recent experiments reported that a flavonoid baicalein can disrupt WT α-synuclein fibrils. However, the underlying disruptive mechanism remains largely elusive, and whether BAC is capable of disrupting mutant α-synuclein fibrils is also unknown. Herein, we performed microsecond molecular dynamics simulations on cryo-EM-determined WT and two familial PD-associated mutant (E46K and H50Q) α-synuclein fibrils with and without baicalein. We find that baicalein destructs WT fibril by disrupting E46-K80 salt-bridge and β-sheets, and by remodeling the inter-protofilament interface. And baicalein can also damage E46K and H50Q mutant fibrils, but to different extents and via different mechanisms. The E46K fibril disruption is initiated from E61-K80 salt-bridge and N-terminal β-sheet, while the H50Q fibril disruption starts from the inter-protofilament interface and N-terminal β-sheet. These results reveal that disruptive effects and modes of baicalein on α-synuclein fibrils are polymorphism-dependent. This study suggests that baicalein may be a potential drug candidate to disrupt both WT and E46K/H50Q mutant α-synuclein fibrils and alleviate the pathological process of PD.
帕金森病（PD）是第二常见的神经退行性疾病，目前尚无治愈方法，其主要特征是α-突触核蛋白纤维状聚集体。α-突触核蛋白聚集在 PD 中的关键作用使其成为潜在的疾病修饰治疗的有吸引力的靶标。α-突触核蛋白纤维的解聚被认为是治疗 PD 的有前途的治疗策略之一。野生型（WT）和突变型α-突触核蛋白纤维表现出不同的多态性，并为 PD 提供了治疗靶点。最近的实验报道，一种黄酮类化合物黄芩素可以破坏 WT α-突触核蛋白纤维。然而，其潜在的破坏机制在很大程度上仍不清楚，并且 BAC 是否能够破坏突变型α-突触核蛋白纤维也是未知的。在此，我们对冷冻电子显微镜确定的 WT 和两种家族性 PD 相关突变（E46K 和 H50Q）α-突触核蛋白纤维进行了微秒分子动力学模拟，同时存在和不存在黄芩素。我们发现黄芩素通过破坏 E46-K80 盐桥和β-片层，以及重塑原纤维间界面，破坏 WT 纤维。黄芩素还可以破坏 E46K 和 H50Q 突变纤维，但破坏程度和机制不同。E46K 纤维的破坏从 E61-K80 盐桥和 N 端β-片层开始，而 H50Q 纤维的破坏从原纤维间界面和 N 端β-片层开始。这些结果表明，黄芩素对α-突触核蛋白纤维的破坏作用和模式是多态依赖性的。这项研究表明，黄芩素可能是一种潜在的药物候选物，可破坏 WT 和 E46K/H50Q 突变型α-突触核蛋白纤维，缓解 PD 的病理过程。
