Primary Nucleation of Polymorphic α-Synuclein Dimers Depends on Copper Concentrations and Definite Copper-Binding Site

Carmia Blacher, Karina Abramov-Harpaz, Yifat Miller

Research output: Contribution to journalArticlepeer-review

Abstract

The primary nucleation process of α-synuclein (AS) that forms toxic oligomeric species is the early stage of the pathological cause of Parkinson’s disease. It is well-known that copper influences this primary nucleation process. While significant efforts have been made to solve the structures of polymorphic AS fibrils, the structures of AS oligomers and the copper-bound AS oligomers at the molecular level and the effect of copper concentrations on the primary nucleation are elusive. Here, we propose and demonstrate new molecular mechanism pathways of primary nucleation of AS that are tuned by distinct copper concentrations and by a specific copper-binding site. We present the polymorphic AS dimers bound to different copper-binding sites at the atomic resolution in high- and low-copper concentrations, using extensive molecular dynamics simulations. Our results show the complexity of the primary nucleation pathways that rely on the copper concentrations and the copper binding site. From a broader perspective, our study proposes a new strategy to control the primary nucleation of other toxic amyloid oligomers in other neurodegenerative diseases.

Original languageEnglish
Article number627
JournalBiomolecules
Volume14
Issue number6
DOIs
StatePublished - 1 Jun 2024

Keywords

  • Parkinson’s disease
  • amyloids
  • metal ions
  • neurodegenerative diseases
  • oligomers
  • polymorphism
  • protein aggregation
  • self-assembly
  • α-synuclein

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology

Fingerprint

Dive into the research topics of 'Primary Nucleation of Polymorphic α-Synuclein Dimers Depends on Copper Concentrations and Definite Copper-Binding Site'. Together they form a unique fingerprint.

Cite this