Baicalein exhibits differential effects and mechanisms towards disruption of α-synuclein fibrils with different polymorphs.

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.