DJ-1 protects against dopamine toxicity: Implications for parkinson's disease and aging

Nirit Lev*, Yael Barhum, Neri S. Pilosof, Debby Ickowicz, Haim Y. Cohen, Eldad Melamed, Daniel Offen

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)215-225
Number of pages11
JournalJournals of Gerontology - Series A Biological Sciences and Medical Sciences
Volume68
Issue number3
DOIs
StatePublished - 1 Mar 2013

Keywords

  • DJ-1
  • Dopamine
  • Oxidative stress
  • Parkinson's disease
  • Reactive oxygen species
  • VMAT2

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