Insights into the Interactions that Trigger the Primary Nucleation of Polymorphic α-Synuclein Dimers

Sapir Lan-Mark, Yifat Miller

Research output: Contribution to journalArticlepeer-review

4 Scopus citations


Parkinson's disease is associated with the accumulation of α-synuclein (AS) aggregates that include polymorphic AS oligomers and polymorphic fibrils. There have been advances in solving the polymorphic state of AS fibrils, both by experimental techniques and molecular modeling tools. Yet, the polymorphic AS oligomers are now considered as the neurotoxic species, thus current and future studies making efforts to solve their structures at the molecular level. Importantly, it is crucial to explore the specific interactions between AS monomers within the dimer that stabilize the dimer and yield nucleation. Herein, we present a first work that probes at the molecular level the specific interactions between monomers in polymorphic AS dimers are derived from AS fibrils by applying molecular modeling tools. Our work reveals that both N-terminal and the non-amyloidogenic component domains play a role in the dimerization of all polymorphic AS dimers. In addition, helices along the N-terminal of AS monomers impede the contacts between AS monomers, thus preventing the nucleation or the dimerization of AS. This work provides insights into several mechanisms of the production of polymorphic AS dimers. Thus, the findings obtained in this work may assist in developing new therapeutic strategies for inhibiting the formation of the early-stage neurotoxic AS dimers.

Original languageEnglish
Pages (from-to)370-378
Number of pages9
JournalACS Chemical Neuroscience
Issue number3
Early online date19 Jan 2022
StateE-pub ahead of print - 19 Jan 2022


  • amyloid aggregation
  • neurodegenerative diseases
  • non-amyloidogenic component
  • Parkinson's disease
  • polymorphism
  • α-synuclein oligomers

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Cognitive Neuroscience
  • Cell Biology


Dive into the research topics of 'Insights into the Interactions that Trigger the Primary Nucleation of Polymorphic α-Synuclein Dimers'. Together they form a unique fingerprint.

Cite this