Understanding alpha-synuclein aggregation propensity in animals and humans

Abstract

Alpha-synuclein (α-syn) aggregation plays a critical role in the pathogenicity of Parkinson's Disease (PD). This study aims to evaluate the aggregation propensity of α-syn fragment peptides designed using the variability found in humans and animals. Thioflavin T (ThT) and transmission electron microscopy (TEM) were used to validate the formation of fibrils to identify important amino acid residues. Human α-syn fragments 51–75, 37–61, 62–86, 76–100, and 116–140 demonstrate a significantly higher tendency to aggregate compared to fragments 1–25, 26–50, and 91–115. All species analyzed of the α-syn 37–61 and 62–86 regions were shown to form fibrils on both ThT and TEM. The α-syn 37–61 and 62–86 fragment regions exhibited a high susceptibility to aggregation, with fibril formation observed in all species. The A53T mutation in several α-syn 37–61 fragments may enhance their propensity for aggregation, suggesting a correlation between this mutation and the capacity for fibril formation. Furthermore, the presence of the non-amyloid-β component (NAC) region, specifically in α-syn 62–86, was consistently observed in several fragments that displayed fibril formation, indicating a potential correlation between the NAC region and the process of fibril formation in α-syn. Finally, the combination of a high quantity of valine and a low quantity of acidic amino acids in these fragments may serve as indicators of α-syn fibril formation.