Unraveling Luteolin's Modulatory Effects on α-Synuclein Aggregation: A Combined Biophysical, Computational, and C....

Parkinson's disease is associated with amyloid fibrillation of alpha-synuclein (α-syn) that involves the aggregation of protein into insoluble fibrils. In this study, we investigate the effect of luteolin (LUT) on α-syn aggregation in vitro, in silico, and in Caenorhabditis elegans. The decrements in light scattering and ThT fluorescence reveal that there is less formation of α-syn aggregates with an increase in the concentration of LUT. Also, a decrease in the ANS fluorescence depicts less exposure of hydrophobic patches in α-syn in the presence of LUT. Far UV CD data shows that LUT resists conversion structure into beta sheets. Dynamic light scattering and transmission electron microscopy revealed that LUT decreases the size and number of fibrils formed. Additionally, LUT reduced RBC hemolysis, indicating its potential therapeutic value in preventing the formation of toxic aggregates. In vivo studies in C. elegans also show that LUT improves the mitochondrial health, reduces reactive oxygen species (ROS), and enhances worm motility. Computational studies provide probable mechanistic insight that LUT interacted with α-syn via hydrophobic and hydrogen interactions, thus limiting the formation of fibrils by masking the sites that might be involved in aggregation. Consequently, LUT is an inhibitor of α-syn aggregation and may be a potential therapeutic agent against Parkinson's disease.