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

[Image: see text] 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 Cu(2+) ions on the aggregation pathway of α-synuclein (α-Syn) proteins, which play a key role in the pathology of Parkinson’s disease. The full spectrum of α-Syn aggregates in the presence and absence of Cu(2+) 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 α-Syn. The formation of annular oligomers was exclusively detected upon incubating α-Syn with Cu(2+) ions. Our findings emphasize the importance of targeting annular α-Syn protein oligomers for therapeutic intervention and their potential role as biomarkers for early detection and monitoring progression of neurodegeneration.