DJ-1 protects against dopamine toxicity: implications for Parkinson's disease and aging

J Gerontol A Biol Sci Med Sci. 2013 Mar;68(3):215-25. doi: 10.1093/gerona/gls147. Epub 2012 Aug 10.


Parkinson's disease (PD) is a common age-related neurodegenerative disorder. Dopamine neurotoxicity, mediated through oxidative stress, is implicated in disease pathogenesis. The vesicular monoamine transporter-2 (VMAT2) transfers dopamine into synaptic vesicles preparing it for exocytotic release and preventing its cytoplasmic oxidation. DJ-1 mutations cause early-onset familial PD. Here, we show that DJ-1 protects dopaminergic neurons and controls the vesicular sequestration of dopamine by upregulating VMAT2. Overexpression of DJ-1 protected cells against dopamine toxicity, reduced oxidative stress, and increased VMAT2 expression and function. Reduced DJ-1 levels resulted in opposite effects. Dopamine vesicular sequestration and its release upon depolarization were dependent on DJ-1 levels. Transcriptional regulation of VMAT2 expression by DJ-1 was confirmed by chromatin immunoprecipitation assay. The results were corroborated in vivo using 6-hydroxydopamine hemiparkinsonian mouse model and transgenic DJ-1 knockout mice. Our experimental data point to a novel potential protective function of DJ-1, which could be used as a therapeutic tool.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic Agents / administration & dosage
  • Adrenergic Agents / adverse effects
  • Aging / metabolism*
  • Animals
  • Blotting, Western
  • Cell Line
  • Disease Models, Animal
  • Dopamine / metabolism*
  • Immunohistochemistry
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Oncogene Proteins / genetics
  • Oncogene Proteins / metabolism*
  • Oxidative Stress
  • Oxidopamine / administration & dosage
  • Oxidopamine / adverse effects
  • Parkinson Disease / metabolism*
  • Peroxiredoxins
  • Protein Deglycase DJ-1
  • RNA, Messenger / metabolism
  • RNA, Small Interfering
  • Reactive Oxygen Species / metabolism
  • Up-Regulation
  • Vesicular Monoamine Transport Proteins / genetics
  • Vesicular Monoamine Transport Proteins / metabolism*


  • Adrenergic Agents
  • Oncogene Proteins
  • RNA, Messenger
  • RNA, Small Interfering
  • Reactive Oxygen Species
  • Slc18a2 protein, mouse
  • Vesicular Monoamine Transport Proteins
  • Oxidopamine
  • Peroxiredoxins
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • PARK7 protein, mouse
  • Protein Deglycase DJ-1
  • Dopamine