Alpha-synuclein (α-syn) is an intrinsically disordered presynaptic protein of the central nervous system, and its aggregation has been described to play a central role in the pathogenicity of Parkinson’s Disease (PD). Although the mechanism is not fully understood, certain mutations in the α-syn protein can increase its susceptibility to oligomerization, fibrillation, and cell permeabilization that creates the cytotoxic effects defined in PD and other forms of neurodegeneration. The α-syn amino acid variability could further our understanding of the mechanisms involved in the aggregation process. This study aims to characterize the aggregation propensity of α-syn via a library of fragment peptides designed based on substitutions (or variability) found in various animal species. We used biophysical assays such as Thioflavin T (ThT) and transmission electron microscopy (TEM) to identify critical amino acid residues for misfolding and aggregation. The α-syn peptide fragments in non-mammalian species are less prone to aggregate compare with mammal sequences analyzed. These non-mammalian peptide fragments included the 1-25 and 26-50 regions in the wild turkey, two-lined caecilian, mainland tiger snake, Tanaka’s snailfish, Greenland sleeper shark, and tiger pufferfish. All 88-113 peptide fragments from different animal species generated fibrils. Region 1-25 was least prone to aggregation for most fragment peptides. The understanding of these identified protein motifs with increased risk for amyloidosis may serve as new potential therapeutic targets for PD and neurodegeneration.
