Insight into the Neuroprotective Mechanisms of Resveratrol: Inhibition of Alpha-Synuclein Fibrillation and its Role in Mitigating Toxicity.

Resveratrol (Res) is a polyphenolic compound with diverse therapeutic properties, including the modulation of inflammatory and oxidative pathways associated with neurodegenerative diseases. Additionally, Res acts as an inhibitor of protein fibrillation. Here, we investigated the effects of Res on α-synuclein (αSN) aggregation, a key protein in Parkinson’s disease (PD) progression. Res effectively inhibited αSN fibrillation in a concentration-dependent manner, especially during the exponential phase. The structural analysis of Res-treated αSN revealed the formation of SDS-sensitive aggregates with non-β structures and an increase in β-turn conformers. Notably, Res rapidly transformed mature fibrillar aggregates into non-toxic conformations with altered secondary structures. Furthermore, introducing Res-treated αSN conformers into fresh monomers prevented further fibrillation. When cells were exposed to perform αSN aggregated in the presence of Res, it not only mitigated cytotoxicity but also reduced reactive oxygen species (ROS) levels, suggesting that Res may induce some non-amyloidogenic structures in αSN and disrupts the amyloidogenesis pathways. The findings support the potential therapeutic application of Res in PD by demonstrating its ability to modulate αSN aggregation and cytotoxicity.