Single-Particle Resolution of Copper-Associated Annular α-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 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 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 α-Syn. The formation of annular oligomers was exclusively detected upon incubating α-Syn with Cu2+ 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.

Detection of Cu2+ Ions with GGH Peptide Realized with Si-Nanoribbon ISFET.

The presence of heavy metal ions such as copper in the human body at certain concentrations and specific conditions can lead to the development of different diseases. The currently available analytical detection methods remain expensive, time-consuming, and often require sample pre-treatment. The development of specific and quantitative, easy-in-operation, and cost-effective devices, capable of monitoring the level of Cu2+ ions in environmental and physiological media, is necessary. We use silicon nanoribbon (SiNR) ion-sensitive field effect transistor (ISFET) devices modified with a Gly-Gly-His peptide for the detection of copper ions in a large concentration range. The specific binding of copper ions causes a conformational change of the ligand, and a deprotonation of secondary amine groups. By performing differential measurements, we gain a deeper insight into the details of the ion-ligand interaction. We highlight in particular the importance of considering non-specific interactions to explain the sensors' response.