Brazilin Inhibits α-Synuclein Fibrillogenesis, Disrupts Mature Fibrils, and Protects against Amyloid-Induced Cytotoxicity

The inhibitory effect of brazilin against alpha-synuclein (alpha-syn) fibrillogenesis, disruption effect against mature fibrils, and the following cytotoxicity were examined by systematical biochemical, biophysical, cellular biological, and molecular simulation experiments. It is found that brazilin inhibited alpha-syn fibrillogenesis and disrupted the performed fibrils with a concentration-dependent manner. Moreover, cellular experimental data showed that brazilin effectively reduced the cytotoxicity induced by alpha-syn aggregates. Finally, molecular dynamics simulations were performed to explore the interactions between brazilin and alpha-syn pentamer. It is found that brazilin directly interacts with alpha-syn pentamer, and the hydrophobic interactions are favorable for brazilin binding with the alpha-syn pentamer, while the electrostatic part provides adverse effects. Three binding regions were identified to inhibit alpha-syn fibrillogenesis or disrupt the preformed aggregates. Furthermore, six important residues (i.e., G51, V52, A53, E61, V66, and K80) of alpha-syn were also identified. We expected that brazilin is an effective agent against alpha-syn fibrillogenesis and associated cytotoxicity.