The aggregation kinetics of α-Synuclein is highly dependent on the protein dynamics in the native state

The aggregation of α-synuclein (Syn) is a hallmark of Parkinson disease (PD) and its misfolding and self-assembly into fibrils play a central role in the pathogenesis of the disease1. Recent studies have highlighted the impact of genetic mutations (A30P, H50Q and A53T) on Syn structure and its aggregation propensity2. However, the influence of the native conformer distribution of Syn and its mutants on the aggregation rate remains unclear. This study aims to investigate, by using biophysical techniques in solution, the correlation between dynamics properties of Syn and its familiar variants and their aggregation propensity. Our results showed that at the native state, the A53T mutation, which induces a destabilized and relaxed monomeric state, leads to a significantly fast aggregation rate, while the H50Q mutation, which retains a compact conformation, results in a slow aggregation process. The A30P mutant, which never undergoes amyloid fibril formation, exhibits a fast equilibrium between the different conformers. Here, we proved that different native conformers exhibit distinct aggregation properties, influencing the rate and the structure of the aggregates formed. These findings provide important insights into the role of Syn native conformation and the correlation with protein aggregation propensity. This understanding is crucial for developing targeted therapies that specifically address the structural factors driving aggregation.