Dopamine and the dopamine oxidation product 5,6-dihydroxylindole promote distinct on-pathway and off-pathway aggregation of alpha-synuclein in a pH-dependent manner

J Mol Biol. 2009 Apr 3;387(3):771-85. doi: 10.1016/j.jmb.2009.02.007. Epub 2009 Feb 11.


The deposition of alpha-synuclein (alpha-syn) aggregates in dopaminergic neurons is a key feature of Parkinson's disease. While dopamine (DA) can modulate alpha-syn aggregation, it is unclear which other factors can regulate the actions of DA on alpha-syn. In this study, we investigated the effect of solution conditions (buffer, salt and pH) on the oligomerization of alpha-syn by DA. We show that alpha-syn oligomerization is dependent on the oxidation of DA into reactive intermediates. Under acidic pH conditions, DA is stable, and DA-mediated oligomerization of alpha-syn is inhibited. From pH 7.0 to pH 11.0, DA is unstable and undergoes redox reactions, promoting the formation of SDS-resistant soluble oligomers of alpha-syn. We show that the reactive intermediate 5,6-dihydroxylindole mediates the formation of alpha-syn soluble oligomers under physiological conditions (pH 7.4). In contrast, under acidic conditions (pH 4.0), 5,6-dihydroxylindole promotes the formation of SDS-resistant insoluble oligomers that further associate to form sheet-like fibrils with beta-sheet structure that do not bind the dye thioflavin T. These results suggest that distinct reactive intermediates of DA, and not DA itself, interact with alpha-syn to generate the alpha-syn aggregates implicated in Parkinson's disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antioxidants / chemistry
  • Buffers
  • Dopamine* / chemistry
  • Dopamine* / metabolism
  • Humans
  • Hydrogen-Ion Concentration*
  • Indoles* / chemistry
  • Indoles* / metabolism
  • Molecular Structure
  • Oxidation-Reduction
  • Parkinson Disease / metabolism
  • Protein Folding
  • Protein Structure, Secondary
  • Salts / chemistry
  • Spectroscopy, Fourier Transform Infrared
  • X-Ray Diffraction
  • alpha-Synuclein / chemistry*
  • alpha-Synuclein / metabolism*
  • alpha-Synuclein / ultrastructure


  • Antioxidants
  • Buffers
  • Indoles
  • Salts
  • alpha-Synuclein
  • Dopamine
  • 5,6-dihydroxyindole