Small molecule oxidation products trigger disease-associated protein misfolding

Acc Chem Res. 2006 Sep;39(9):611-9. doi: 10.1021/ar0500766.


Oxidative stress and inflammation are risk factors for both the development of alpha-synucleinopathies, such as Parkinson's disease and dementia with Lewy bodies, and Alzheimer's disease, the two most common neurodegenerative disorders. These diseases are associated with the neurotoxic deposition of misassembled alpha-synuclein and amyloid-beta (Abeta) peptides, respectively. Both occur sporadically, that is, without detectable disease-related mutations, in the vast majority of cases. Small molecule oxidation products, especially secosterols derived from cholesterol and 4-hydroxynonenal derived from lipid peroxidation, found in afflicted brains, accelerate the misassembly of both Abeta and alpha-synuclein. This Account explores the mechanism of small molecule oxidation product-mediated protein misassembly and possible intervention strategies.

Publication types

  • Review

MeSH terms

  • Aldehydes / metabolism
  • Alzheimer Disease / metabolism
  • Amyloid / metabolism
  • Atherosclerosis / metabolism
  • Biopolymers
  • Cholesterol / metabolism
  • Humans
  • Inflammation / metabolism
  • Lipid Peroxidation
  • Oxidation-Reduction
  • Oxidative Stress
  • Protein Folding*
  • alpha-Synuclein / metabolism


  • Aldehydes
  • Amyloid
  • Biopolymers
  • alpha-Synuclein
  • Cholesterol