The lipid peroxidation metabolite 4-oxo-2-nonenal cross-links alpha-synuclein causing rapid formation of stable oligomers

Biochem Biophys Res Commun. 2009 Jan 23;378(4):872-6. doi: 10.1016/j.bbrc.2008.12.005. Epub 2008 Dec 12.


Recently, the aldehyde 4-oxo-2-nonenal (ONE) was identified as a product of lipid peroxidation and found to be an effective protein modifier. In this in vitro study we investigated structural implications of the interaction between ONE and alpha-synuclein, a protein which forms intraneuronal inclusions in neurodegenerative disorders such as Parkinson's disease and dementia with Lewy bodies. Our results demonstrate that ONE induced an almost complete conversion of monomeric alpha-synuclein into 40-80 nm wide and 6-8 nm high soluble beta-sheet-rich oligomers with a molecular weight of approximately 2000 kDa. Furthermore, the ONE-induced alpha-synuclein oligomers displayed a high stability and were not sensitive to treatment with sodium dodecyl sulfate, indicating that ONE stabilized the oligomers by cross-linking individual alpha-synuclein molecules. Despite prolonged incubation the oligomers did not continue to aggregate into a fibrillar state, thus suggesting that these alpha-synuclein species were not on a fibrillogenic pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aldehydes / chemistry
  • Aldehydes / metabolism*
  • Amyloid / chemistry
  • Amyloid / metabolism
  • Chromatography, High Pressure Liquid
  • Humans
  • Lipid Peroxidation*
  • Microscopy, Atomic Force
  • Molecular Weight
  • Parkinsonian Disorders / metabolism
  • Protein Conformation
  • Sodium Dodecyl Sulfate / chemistry
  • alpha-Synuclein / chemistry
  • alpha-Synuclein / metabolism*


  • 4-oxo-2-nonenal
  • Aldehydes
  • Amyloid
  • alpha-Synuclein
  • Sodium Dodecyl Sulfate