Natural compound safranal driven inhibition and dis-aggregation of α-synuclein fibrils

Self-assembly of alpha-synuclein (alpha-Syn) is linked with a variety of neurodegenerative diseases collectively called as alpha-synucleiopathies. Therefore, discovering suitable inhibitors for this self-association process of alpha-Syn is a subject of intense research. In this background, we have demonstrated here that the natural compound, Safranal, delays/inhibits alpha-Syn fibrillation/aggregation, and we have also characterized its mode of action. The alpha-Syn fibrillation/aggregation kinetics studies in combination with TEM studies demonstrated that Safranal effectively inhibits alpha-Syn fibrillation/aggregation. NMR studies revealed that Safranal binds with alpha-Syn and stabilizes the monomeric protein. ANS fluorescence and CD measurements indicated that Safranal binds to the hydrophobic residues of the protein and causes delay in the formation of beta-sheet rich structures which are crucial for the fibrillation to occur. The results obtained from fluorescence quenching, NMR and ANS binding assays, when analysed taking into consideration the molecular structure of Safranal provide valuable insights into the mechanism of inhibition of alpha-Syn fibrillation/aggregation. We infer that inhibition of alpha-Syn fibrillation/aggregation is primarily driven by hydrophobic interactions between Safranal and the protein. Further, Safranal is also seen to disaggregates pre-formed alpha-Syn fibrils. These findings implicate that Safranal could become a potent therapeutic intervention in Parkinson's disease and other protein aggregation related disorders. (C) 2019 Published by Elsevier B.V.