4.6 Article

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

Journal

ACS CHEMICAL NEUROSCIENCE
Volume 13, Issue 9, Pages 1410-1421

Publisher

AMER CHEMICAL SOC
DOI: 10.1021/acschemneuro.2c00021

Keywords

neurodegeneration; peptide self-assembly; metal-protein interactions; atomic force microscopy; Raman spectroscopy; molecular dynamics simulations

Funding

  1. Swiss National Science Foundation (SNF) Spark funding [CRSK-2-190330]
  2. SNF [PMPDP3_164425]
  3. Science Foundation Ireland (SFI) [12/RC/2275_P2]
  4. Swiss National Science Foundation (SNF) [CRSK-2_190330, PMPDP3_164425] Funding Source: Swiss National Science Foundation (SNF)

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This study investigates the concentration-dependent effect of Cu2+ ions on the aggregation pathway of alpha-synuclein (α-Syn) proteins. The results show that Cu2+ ions induce the formation of annular oligomers, highlighting their potential as therapeutic targets and biomarkers for Parkinson's disease and 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.

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