title: DJ-1 deficiency in astrocytes selectively enhances mitochondrial Complex I inhibitor-induced neurotoxicity.
abstract: 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.
authors.affiliation: Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15260, USA.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Mullett
authors.forename: David A
authors.initials: DA
authors.lastname: Hinkle
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D018920:Coculture Techniques; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors*; D009474:Neurons; D009498:Neurotoxins / Q000494:pharmacology; D015513:Oncogene Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D054464:Peroxiredoxins; D000071617:Protein Deglycase DJ-1; D034741:RNA, Small Interfering / Q000378:metabolism; D013997:Time Factors; D014162:Transfection / Q000379:methods
chemical_list: D017077:Culture Media, Conditioned; D004791:Enzyme Inhibitors; D005904:Glial Fibrillary Acidic Protein; D008869:Microtubule-Associated Proteins; C079240:Mtap2 protein, mouse; D009097:Multienzyme Complexes; D009498:Neurotoxins; D015513:Oncogene Proteins; D034741:RNA, Small Interfering; D054464:Peroxiredoxins; C503466:PARK7 protein, mouse; D000071617:Protein Deglycase DJ-1; D005978:Glutathione