Single-Particle Resolution of Copper-Associated Annular alpha-Synuclein Oligomers Reveals Potential Therapeutic Targets of Neurodegeneration

Metal ions stabilize protein-protein interactions and can modulate protein aggregation. Here, using liquid-based atomic force microscopy and molecular dynamics simulations, we study the concentration-dependent effect of Cu2+ ions on the aggregation pathway of alpha-synudein (alpha-Syn) proteins, which play a key role in the pathology of Parkinson's disease. The full spectrum of alpha-Syn aggregates in the presence and absence of Cu2+ ions from monomers to mature fibrils was resolved and quantified at the gold-water interface. Raman spectroscopy confirmed the atomic force microscopy (AFM) findings on the heterogeneity in aggregated states of alpha-Syn. The formation of annular oligomers was exclusively detected upon incubating alpha-Syn with Cu2+ ions. Our findings emphasize the importance of targeting annular alpha-Syn protein oligomers for therapeutic intervention and their potential role as biomarkers for early detection and monitoring progression of neurodegeneration.