Oxidative insults induce DJ-1 upregulation and redistribution: implications for neuroprotection.
Oxidative stress is implicated in the pathogenesis of central nervous system damage in neurodegenerative diseases as well as in normal aging. Parkinson's disease (PD) is one of the most common age-related neurodegenerative diseases caused by both environmental and inherited factors. DJ-1 mutations were recently identified in familial PD. The aim of this study was to elucidate the effects of the neurotoxins rotenone and 6-hydroxydopamine that lead to intracellular reactive oxygen species (ROS) on DJ-1 expression levels and intracellular distribution. The sensitivity to oxidative insults induced by rotenone, 6-hydroxydopamine and hydrogen peroxide of transfected human neuroblastoma cells that were engineered to have increased or decreased DJ-1 levels was also examined. Overexpression of DJ-1 resulted in increased cellular resistance to these insults and reduced intracellular ROS. Contrary effects were achieved when DJ-1 levels were reduced by siRNA. Exposure of naïve neuroblastoma cells to rotenone or 6-hydroxydopamine induced upregulation of DJ-1 mRNA and protein levels. Pretreatment with an antioxidant abolished these changes, implying that the upregulation of DJ-1 resulted from oxidative stress. Neurotoxins exposure not only induced upregulation of DJ-1, but also induced cellular redistribution of DJ-1 manifested by translocation of DJ-1 into the mitochondria. These results may imply that DJ-1 plays an important role in the neuronal defense mechanism against oxidative insults.
Lev
Nirit
N
Laboratory of Neuroscience and Department of Neurology, Rabin Medical Center, FMRC, Tel Aviv University, Petah-Tikva, Israel. lev.nirit@gmail.com
Ickowicz
Debby
D
Melamed
Eldad
E
Offen
Daniel
D
D015153:Blotting, Western; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D018613:Microscopy, Confocal; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000096:biosynthesis; D018696:Neuroprotective Agents / Q000494:pharmacology*; D015513:Oncogene Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism*; D016877:Oxidants / Q000633:toxicity; D018384:Oxidative Stress / Q000235:genetics / Q000502:physiology*; D016627:Oxidopamine / Q000633:toxicity; D000071617:Protein Deglycase DJ-1; D012313:RNA / Q000096:biosynthesis; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012402:Rotenone / Q000633:toxicity; D013565:Sympatholytics / Q000633:toxicity; D014162:Transfection; D014475:Uncoupling Agents / Q000633:toxicity; D015854:Up-Regulation / Q000187:drug effects
D018076:DNA, Complementary; D047908:Intracellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D015513:Oncogene Proteins; D016877:Oxidants; D017382:Reactive Oxygen Species; D013565:Sympatholytics; D014475:Uncoupling Agents; D012402:Rotenone; D012313:RNA; D016627:Oxidopamine; D006861:Hydrogen Peroxide; C105131:PARK7 protein, human; D000071617:Protein Deglycase DJ-1