Molecular insights into alpha-synuclein interaction with individual human core histones, linker histone, and dsDNA

alpha-Synuclein (alpha S) plays a key role in Parkinson's disease (PD). The alpha S nuclear role, its binding affinity and specificity to histones and dsDNA remains unknown. Here, we have measured the binding affinity (Kd) between alpha S wild-type (wt) and PD-specific alpha S S129-phosphorylation mimicking (S129E) mutant with full-length and flexible tail truncated individual core histones (H2a, H2b, H3, and H4), linker histone (H1), and carried out alpha S-dsDNA interaction studies. This study revealed that alpha S(wt) interacts specifically with N-terminal flexible tails of histone H3, H4, and flexible tails of H1. The alpha S(S129E) mutant recognizes histones similar to alpha S(wt) but binds with higher affinity. Intriguingly, alpha S(S129E) showed a binding affinity for control proteins (bovine serum albumin and lysozyme), while no interaction was seen for alpha S(wt). Based on our above observation, we contemplate that the physio-chemical properties of alpha S with S129-phosphorylation has changed compared to alpha S(wt), resulting in interaction for other proteins, which is the basis for Lewy body formation. Besides, this study showed alpha S binding to dsDNA is weak and nonspecific. Overall, alpha S specificity for histone binding suggests that its nuclear role is possibly driven through histone interaction.