DJ-1 protects against dopamine toxicity

Nirit Lev*, Debby Ickowicz, Yael Barhum, Shaul Lev, Eldad Melamed, Daniel Offen

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Parkinson's disease (PD) is a slowly progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons. Dopamine is a highly toxic compound leading to generation of reactive oxygen species (ROS). DJ-1 mutations lead to early-onset inherited PD. Here, we show that DJ-1 protects against dopamine toxicity. Dopamine-exposure led to upregulation of DJ-1. Overexpression of DJ-1 increased cell resistance to dopamine toxicity and reduced intracellular ROS. Contrary effects were achieved when DJ-1 levels were reduced by siRNA. Similarly, in vivo striatal administration of 6-hydroxydopamine led to upregulation of DJ-1. Upregulation of DJ-1 was mediated by the MAP kinases pathway through activation of ERK 1, 2 in vitro and in vivo. Hence, oxidative stress, generated by free cytoplasmic dopamine, leads to upregulation of DJ-1 through the MAP kinases pathway. This mechanism elucidates how mutations in DJ-1 prompt PD and imply that modulation of DJ-1 may serve as a novel neuroprotective modality.

Original languageEnglish
Pages (from-to)151-160
Number of pages10
JournalJournal of Neural Transmission
Volume116
Issue number2
DOIs
StatePublished - Feb 2009

Keywords

  • DJ-1
  • Dopamine
  • MAP kinases
  • Oxidative stress
  • Parkinson's disease

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