Molecular insights into diosgenin's role in preventing protein aggregation in neurodegenerative diseases

Neurodegenerative disorders (ND) such as Parkinson's and Alzheimer's progressively impair the nervous system, leading to cognitive deterioration and motor dysfunction. A primary factor in these diseases is the accumulation of misfolded protein aggregates, which interfere with cellular processes and ultimately result in neuronal death. Preventing the formation of these toxic aggregates has the potential to protect neurons and slow the advancement of disease. This study examined the impact of diosgenin on protein aggregation, utilizing human serum albumin (HSA) as model protein. Diosgenin reduced ThT fluorescence by 64.35 % and decreased turbidity by 62.61 %, indicating a notable suppression of protein aggregation. The % α-helix in HSA experienced a decline from 57.68 % to 8.82 %, but diosgenin treatment restored it to 43.89 %. Binding studies demonstrated that diosgenin interacts with HSA with -11.0 kcal/mol binding energy, facilitated by van der Waals, hydrophobic and hydrogen bonding interactions, and stability of HSA-diosgenin complex was also validated using molecular simulations. To further elucidate the aggregation inhibition mechanism by diosgenin, advanced molecular dynamics simulations were employed. Diosgenin increased the solvent accessibility of the HSA_282-292 oligomers, reduced β-sheet formation, and prevented H-bond interactions, key factors in aggregate formation. Molecular simulation of Aβ oligomers (Aβ_16-22) also showed the diosgenin prevents oligomerization and β-sheet formation. We show that diosgenin presents a promising alternative due to its ability to stabilize protein structures and inhibit protein aggregation, making it a potential therapeutic candidate for NDs. However, further experimental validation in animal models is necessary to confirm diosgenin's anti-aggregation effects, particularly of amyloid-forming proteins.