Work

Investigating the impact of Cu2+ on α-synuclein aggregation: A single-molecule approach

Year: 2025

Type: article

Abstract: Parkinson's disease (PD) is a prevalent neurodegenerative disorder characterized by the abnormal aggregation of α-synuclein. This study investigated the impact of Cu 2+ ions on α-synuclein aggregation in oligomer distribution using two single-molecule techniques. The aggregation of α-synuclein monomers with and without Cu 2+ revealed that Cu 2+ accelerated the formation of ThT-positive β-sheet structured aggregates. Nanopipettes of varying diameters from to 7 to 134 nm were employed to characterize the oligomers formed during the lag phase, demonstrating that Cu 2+ generated a wider range of oligomers from 10 nm 3 to 20,000 nm 3 over time. Confocal fluorescence spectroscopy analysis of ThT-positive fibrils in the plateau phase showed that Cu 2+ induces larger oligomers and fewer in number. The introduction of preformed seeds to the control and Cu 2+ -containing samples further accelerated the aggregation. The combination of seeds and Cu 2+ produced structurally distinct oligomers, with seeds catalyzing the formation of small oligomers that detach from the parent fibers and Cu 2+ , promoting the formation of larger oligomers. These results reveals that seeds and Cu 2+ act synergistically, with two different aggregation pathways coexisting in the early phase, leading to an intermediate composition of fibers and clusters at the end of aggregation.

Source: International Journal of Biological Macromolecules

DOI: 10.1016/j.ijbiomac.2025.142161

Authors: Imad Abrao-Nemeir, Saly Charles-Achille, Bastien Cayrol, Sebastien Balme