Structural and functional characterization of two alpha-synuclein strains

Nat Commun. 2013;4:2575. doi: 10.1038/ncomms3575.

Abstract

α-Synuclein aggregation is implicated in a variety of diseases including Parkinson's disease, dementia with Lewy bodies, pure autonomic failure and multiple system atrophy. The association of protein aggregates made of a single protein with a variety of clinical phenotypes has been explained for prion diseases by the existence of different strains that propagate through the infection pathway. Here we structurally and functionally characterize two polymorphs of α-synuclein. We present evidence that the two forms indeed fulfil the molecular criteria to be identified as two strains of α-synuclein. Specifically, we show that the two strains have different structures, levels of toxicity, and in vitro and in vivo seeding and propagation properties. Such strain differences may account for differences in disease progression in different individuals/cell types and/or types of synucleinopathies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Escherichia coli / genetics
  • Escherichia coli / metabolism
  • Humans
  • Neurons / cytology
  • Neurons / drug effects*
  • Protein Folding
  • Protein Isoforms / chemistry
  • Protein Isoforms / genetics
  • Protein Isoforms / pharmacology
  • Protein Multimerization
  • Protein Structure, Secondary
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Recombinant Proteins / pharmacology
  • Scattering, Small Angle
  • Spectroscopy, Fourier Transform Infrared
  • X-Ray Diffraction
  • alpha-Synuclein / chemistry*
  • alpha-Synuclein / genetics
  • alpha-Synuclein / pharmacology

Substances

  • Protein Isoforms
  • Recombinant Proteins
  • alpha-Synuclein