Hydroxycinnamic acids mediated modulation of α-Synuclein fibrillation: Biophysical insights

The fibrillation of α-synuclein (α-Syn) is considered a major contributor to Parkinson's disease (PD). Recent therapeutic measures have focused on inhibiting the fibrillation of α-Syn using various small molecules. We report here the effects of two different hydroxycinnamic acids; chlorogenic acid and sinapic acid on α-Syn fibrillation and have also discussed the mechanistic insights into their mode of modulation. The fluorescence spectroscopy shows that the two hydroxycinnamic acids bind with α-Syn with moderate affinity. Molecular docking studies provide a detailed insights into binding at the residue level and isothermal titration calorimetry reveals specific interactions, like hydrogen bonding, hydrophobic interactions, and van der Waals forces involved in the binding process. Fibrillation kinetics and transmission microscopic studies demonstrated that both chlorogenic acid and sinapic acid attenuate α-Syn fibrillation in a concentration dependent manner. Circular dichroism spectroscopy shows that these compounds bind with α-Syn and delay its structural transition in β-sheet containing fibrillar structures. Both the compounds are also effective even if added after the onset of fibrillation and the fibrillar species formed in the presence of these acids are unable to induce secondary nucleation in monomeric α-Syn. Such kind of structural and mechanistic insights are extremely crucial for designing therapeutic intervention in PD and other neurodegenerative diseases.