Down regulation of DJ-1 enhances cell death by oxidative stress, ER stress, and proteasome inhibition

Biochem Biophys Res Commun. 2003 Dec 26;312(4):1342-8. doi: 10.1016/j.bbrc.2003.11.056.

Abstract

Mutations in DJ-1 gene have been linked to autosomal recessive early onset parkinsonism (AR-EOP). Although the mechanism of neuronal cell death due to DJ-1 mutation has not been fully elucidated, loss of DJ-1 function was considered to cause the phenotype. Here, we demonstrated that the down regulation of endogenous DJ-1 of the neuronal cell line by siRNA enhanced the cell death which was induced by oxidative stress, ER stress, and proteasome inhibition, but not by pro-apoptotic stimulus. The cell death with hydrogen peroxide was dramatically rescued by over-expression of wild-type DJ-1, but not by that of L166P mutant DJ-1. Furthermore, DJ-1 rescued the cell death caused by over-expression of Pael receptor, which was a substrate of Parkin, another gene product for autosomal recessive juvenile parkinsonism. These results suggest that loss of protective activity of DJ-1 from neuro-toxicity induced by these stresses contributes to neuronal cell death in AR-EOP with mutant DJ-1.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Bacterial Agents / pharmacology
  • Apoptosis*
  • Cell Line
  • Cell Line, Tumor
  • Cysteine Endopeptidases / metabolism*
  • Dose-Response Relationship, Drug
  • Down-Regulation
  • Endoplasmic Reticulum / drug effects
  • Endoplasmic Reticulum / metabolism*
  • Humans
  • Hydrogen Peroxide / pharmacology
  • Intracellular Signaling Peptides and Proteins
  • Kidney / drug effects
  • Kidney / metabolism*
  • Mice
  • Multienzyme Complexes / antagonists & inhibitors
  • Multienzyme Complexes / metabolism*
  • Mutation
  • Neuroblastoma / metabolism*
  • Oncogene Proteins / genetics
  • Oncogene Proteins / metabolism*
  • Oxidative Stress / drug effects
  • Proteasome Endopeptidase Complex
  • Protein Deglycase DJ-1
  • Recombinant Proteins / metabolism
  • Staurosporine / pharmacology
  • Structure-Activity Relationship

Substances

  • Anti-Bacterial Agents
  • Intracellular Signaling Peptides and Proteins
  • Multienzyme Complexes
  • Oncogene Proteins
  • Recombinant Proteins
  • Hydrogen Peroxide
  • PARK7 protein, human
  • Protein Deglycase DJ-1
  • Cysteine Endopeptidases
  • Proteasome Endopeptidase Complex
  • Staurosporine