Salvianolic acid B prevents the amyloid transformation of A53T mutant of α-synuclein

Abstract

Parkinson's disease (PD) is a neurodegenerative disorder involving the progressive loss of dopaminergic neurons in the substantia nigra pars compacta triggered by the accumulation of amyloid aggregates of α-synuclein protein. This study investigates the potential of Salvianolic Acid B (SalB), a water-soluble polyphenol derived from Salvia miltiorrhiza Bunge, in modulating the aggregation of the A53T mutant of α-synuclein (A53T Syn). This mutation is associated with rapid aggregation and a higher rate of protofibril formation in early-onset familial PD. Computational and experimental approaches demonstrated Sal-B effectively prevents the amyloid fibrillation of A53T Syn by interacting with the N-terminal region and NAC domain. Sal-B particularly associates with the KTKEGV motif and NACore segment of A53T Syn by hydrophobic and hydrogen bonding interactions. Replica exchange molecular dynamics (REMD) simulations indicated that Sal-B reduces intramolecular hydrogen bonding and structural transitions into β-sheet rich conformations, thereby lowering the aggregation propensity of A53T Syn. Systematic analysis conducted using biophysical techniques and high-end microscopy has demonstrated significant inhibition in the amyloid transformation of A53T Syn corroborated by a 92 % decrease in ThT maxima at 100 μM Sal-B concentration and microscopic techniques validated the absence of mature fibrillar amyloids. DLS data revealed heterogeneous particle sizes, supporting the formation of smaller unstructured aggregates. These findings underscore Sal-B as a promising therapeutic candidate for PD and related synucleinopathies, warranting further investigation in cellular and animal models to advance potential treatments and early intervention strategies.