Nrf2-mediated protection against 6-hydroxydopamine.
Parkinson's disease (PD) is a neurodegenerative movement disorder characterized by cell loss in the substantia nigra resulting in striatal dopamine depletion. Although the cause of sporadic PD is unknown, oxidative stress is thought to contribute to disease pathogenesis. One mechanism by which cells defend themselves against oxidative stress is through the transcriptional upregulation of cytoprotective genes. Under oxidative stress conditions, the transcription factor NF-E2-related factor (Nrf2) binds to the antioxidant response element (ARE) to induce antioxidant and phase II detoxification enzymes. Here we show that loss of Nrf2-mediated transcription exacerbates vulnerability to the neurotoxin 6-hydroxydopamine (6-OHDA) both in vitro and in vivo. We further demonstrate that activation of the Nrf2-ARE pathway by the known chemical inducer tert-butylhydroquinone can protect against 6-OHDA in vitro. Induction of this pathway by transplantation of astrocytes overexpressing Nrf2 can protect against 6-OHDA-induced damage in the living mouse. This suggests that the Nrf2-ARE pathway is a promising target for therapeutics aimed at reducing or preventing cell death in PD.
Jakel
Rebekah J
RJ
Department of Pharmaceutical Sciences, School of Pharmacy, University of Wisconsin-Madison, WI 53705, USA.
Townsend
Jessica A
JA
Kraft
Andrew D
AD
Johnson
Jeffrey A
JA
D000818:Animals; D001253:Astrocytes / Q000502:physiology; D016923:Cell Death / Q000187:drug effects; D017690:Cell Transplantation / Q000379:methods; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004281:Docosahexaenoic Acids / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D005260:Female; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006873:Hydroquinones / Q000494:pharmacology; D020287:In Situ Nick-End Labeling; D051379:Mice; D018345:Mice, Knockout; D050984:NF-E2 Transcription Factor, p45 Subunit / Q000172:deficiency / Q000502:physiology*; D009474:Neurons / Q000187:drug effects*; D009498:Neurotoxins / Q000633:toxicity*; D016627:Oxidopamine / Q000633:toxicity*; D014162:Transfection; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D006873:Hydroquinones; D050984:NF-E2 Transcription Factor, p45 Subunit; D009498:Neurotoxins; C494693:Nfe2 protein, mouse; D049452:Green Fluorescent Proteins; D004281:Docosahexaenoic Acids; D016627:Oxidopamine; C018855:2-tert-butylhydroquinone; D014446:Tyrosine 3-Monooxygenase