DOPAL derived alpha-synuclein oligomers impair synaptic vesicles physiological function

Sci Rep. 2017 Jan 13:7:40699. doi: 10.1038/srep40699.


Parkinson's disease is a neurodegenerative disorder characterized by the death of dopaminergic neurons and by accumulation of alpha-synuclein (aS) aggregates in the surviving neurons. The dopamine catabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL) is a highly reactive and toxic molecule that leads to aS oligomerization by covalent modifications to lysine residues. Here we show that DOPAL-induced aS oligomer formation in neurons is associated with damage of synaptic vesicles, and with alterations in the synaptic vesicles pools. To investigate the molecular mechanism that leads to synaptic impairment, we first aimed to characterize the biochemical and biophysical properties of the aS-DOPAL oligomers; heterogeneous ensembles of macromolecules able to permeabilise cholesterol-containing lipid membranes. aS-DOPAL oligomers can induce dopamine leak in an in vitro model of synaptic vesicles and in cellular models. The dopamine released, after conversion to DOPAL in the cytoplasm, could trigger a noxious cycle that further fuels the formation of aS-DOPAL oligomers, inducing neurodegeneration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3,4-Dihydroxyphenylacetic Acid / analogs & derivatives*
  • 3,4-Dihydroxyphenylacetic Acid / pharmacology
  • Animals
  • Biological Transport / drug effects
  • Cell Line
  • Cell Membrane / metabolism
  • Humans
  • Magnetic Resonance Spectroscopy
  • Mice
  • Neurons / drug effects
  • Neurons / metabolism
  • Neurons / ultrastructure
  • Permeability
  • Protein Aggregates
  • Protein Aggregation, Pathological
  • Protein Binding
  • Protein Multimerization / drug effects*
  • Synaptic Vesicles / drug effects*
  • Synaptic Vesicles / metabolism*
  • Tandem Mass Spectrometry
  • alpha-Synuclein / chemistry
  • alpha-Synuclein / metabolism*


  • Protein Aggregates
  • alpha-Synuclein
  • 3,4-Dihydroxyphenylacetic Acid
  • 3,4-dihydroxyphenylacetaldehyde