DJ-1 deficiency in astrocytes selectively enhances mitochondrial Complex I inhibitor-induced neurotoxicity

J Neurochem. 2011 May;117(3):375-87. doi: 10.1111/j.1471-4159.2011.07175.x. Epub 2011 Jan 28.


Parkinson's disease (PD) brains show evidence of mitochondrial respiratory Complex I deficiency, oxidative stress, and neuronal death. Complex I-inhibiting neurotoxins, such as the pesticide rotenone, cause neuronal death and parkinsonism in animal models. We have previously shown that DJ-1 over-expression in astrocytes augments their capacity to protect neurons against rotenone, that DJ-1 knock-down impairs astrocyte-mediated neuroprotection against rotenone, and that each process involves astrocyte-released factors. To further investigate the mechanism behind these findings, we developed a high-throughput, plate-based bioassay that can be used to assess how genetic manipulations in astrocytes affect their ability to protect co-cultured neurons. We used this bioassay to show that DJ-1 deficiency-induced impairments in astrocyte-mediated neuroprotection occur solely in the presence of pesticides that inhibit Complex I (rotenone, pyridaben, fenazaquin, and fenpyroximate); not with agents that inhibit Complexes II-V, that primarily induce oxidative stress, or that inhibit the proteasome. This is a potentially PD-relevant finding because pesticide exposure is epidemiologically-linked with an increased risk for PD. Further investigations into our model suggested that astrocytic GSH and heme oxygenase-1 antioxidant systems are not central to the neuroprotective mechanism.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Astrocytes / drug effects*
  • Cells, Cultured
  • Cerebral Cortex / cytology
  • Coculture Techniques
  • Culture Media, Conditioned / pharmacology
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • Enzyme Inhibitors / pharmacology*
  • Gene Expression Regulation / drug effects
  • Glial Fibrillary Acidic Protein / metabolism
  • Glutathione / metabolism
  • Mice
  • Microtubule-Associated Proteins / metabolism
  • Multienzyme Complexes / antagonists & inhibitors*
  • Neurons
  • Neurotoxins / pharmacology
  • Oncogene Proteins / deficiency*
  • Oncogene Proteins / genetics
  • Oncogene Proteins / metabolism
  • Oxidative Stress / drug effects
  • Peroxiredoxins
  • Protein Deglycase DJ-1
  • RNA, Small Interfering / metabolism
  • Time Factors
  • Transfection / methods


  • Culture Media, Conditioned
  • Enzyme Inhibitors
  • Glial Fibrillary Acidic Protein
  • Microtubule-Associated Proteins
  • Mtap2 protein, mouse
  • Multienzyme Complexes
  • Neurotoxins
  • Oncogene Proteins
  • RNA, Small Interfering
  • Peroxiredoxins
  • PARK7 protein, mouse
  • Protein Deglycase DJ-1
  • Glutathione