Oxidative dimer formation is the critical rate-limiting step for Parkinson's disease alpha-synuclein fibrillogenesis

Biochemistry. 2003 Jan 28;42(3):829-37. doi: 10.1021/bi026528t.


Intraneuronal deposition of alpha-synuclein as fibrils and oxidative stress are both implicated in the pathogenesis of Parkinson's disease. We found that the critical rate-limiting step in nucleation of alpha-synuclein fibrils under physiological conditions is the oxidative formation and accumulation of a dimeric, dityrosine cross-linked prenucleus. Dimer formation is accelerated for the pathogenic A30P and A53T mutant alpha-synucleins, because of their greater propensity to self-interact, which is reflected in the smaller values of the osmotic second virial coefficient compared to that of wild-type synuclein. Our finding that oxidation is an essential step in alpha-synuclein aggregation supports a mechanism of Parkinson's disease pathogenesis in which the separately studied pathogenic factors of oxidative stress and alpha-synuclein aggregation converge at the critical step of alpha-synuclein dimer formation.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amino Acid Substitution / genetics
  • Chromatography, High Pressure Liquid
  • Cross-Linking Reagents / metabolism
  • Dimerization
  • Humans
  • Hydrogen-Ion Concentration
  • Light
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Nerve Tissue Proteins / ultrastructure
  • Osmolar Concentration
  • Osmotic Pressure
  • Oxidation-Reduction
  • Oxidative Stress
  • Parkinson Disease / etiology
  • Parkinson Disease / metabolism*
  • Parkinson Disease / pathology
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Scattering, Radiation
  • Spectrometry, Mass, Electrospray Ionization
  • Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
  • Spectrophotometry, Ultraviolet
  • Synucleins
  • Temperature
  • Tyrosine / analogs & derivatives*
  • Tyrosine / metabolism
  • alpha-Synuclein


  • Cross-Linking Reagents
  • Nerve Tissue Proteins
  • Protein Isoforms
  • SNCA protein, human
  • Synucleins
  • alpha-Synuclein
  • Tyrosine
  • dityrosine