Mapping the Role of Monomer Conformation in the Amyloid Formation of α-Synuclein Splice Variants

Amyloid formation of the protein α-synuclein (αSyn) is a hallmark of pathogenesis in Parkinson's disease, multiple system atrophy, and dementia with Lewy bodies. Research has predominantly focused on the 140-amino acid αSyn sequence, yet the <i>SNCA</i> gene can be alternatively spliced to generate several different isoforms, including αSynΔ3, αSynΔ5, and αSynΔ3Δ5. Here, we have used experimental and computational approaches to characterize these splice variants, in addition to the full-length αSyn, in terms of their monomer conformation and amyloid propensity as a function of changes in ionic strength. Kinetic analysis of amyloid formation, flow-induced dispersion analysis, and coarse-grained molecular dynamics simulations reveal a striking correlation between monomer conformation and the rate of secondary nucleation of amyloid formation, and we show that this is governed by both global conformation of the polypeptide chain and local contacts in the hydrophobic core domain and acidic C-terminal domain. By combining changes in amino acid sequences and ionic strength, our analysis reveals the importance of local contacts and long-range electrostatic interactions in driving the kinetics of amyloid formation of αSyn.