Inhibition of α-Synuclein fibrillation by curcumin and difluoro boron derivatized curcumin complexes in aqueous environment

Abstract

Fibrillation of α-Synuclein (α-Syn) is a key pathogenic event in Parkinson’s disease (PD). In the present work, we have investigated the effects of Curcumin (Cur) and its derivatives; curcumin-BF2 (Cur-BF2) and iodinated-curcumin-BF2 (I-Cur-BF2) on the inhibition of α-Syn fibrillation. The ITC results showed that all three curcumins bind via a combination of both H-bonding and hydrophobic interactions. The fibrillation kinetics studies demonstrate that Cur and its derivatives inhibit its fibrillation and increase α-Syn solubility. I-Cur-BF2 is the most efficient in fibrillation inhibition followed by Cur-BF2 and Cur, attributed to the ability to increase the hydrophobic interactions. Transmission electron microscopy (TEM) confirmed the presence of thinner, lesser, and smaller α-Syn fibrils in the presence of the Cur and its derivatives. The fibrillar aggregates formed in the presence of Cur and its derivatives are unable to induce fibrillation in healthy monomeric α-Syn. Cur and its derivatives also have the ability to disaggregate elongating and preformed fibrils and sequester them in globular condensates which prevent further fibrillation in α-Syn. Together, our findings provide unique information about the mechanism of binding of Cur and its derivatives with α-Syn and demonstrate that curcumin compounds regulate α-Syn amyloid formation in the aqueous environment.