title: Oxidative modification of peroxiredoxin is associated with drug-induced apoptotic signaling in experimental models of Parkinson disease.
abstract: The aim of this study was to investigate changes in protein profiles during the early phase of dopaminergic neuronal death using two-dimensional gel electrophoresis in conjunction with mass spectrometry. Several protein spots were identified whose expression was significantly altered following treatment of MN9D dopaminergic neuronal cells with 6-hydroxydopamine (6-OHDA). In particular, we detected oxidative modification of thioredoxin-dependent peroxidases (peroxiredoxins; PRX) in treated MN9D cells. Oxidative modification of PRX induced by 6-OHDA was blocked in the presence of N-acetylcysteine, suggesting that reactive oxygen species (ROS) generated by 6-OHDA induce oxidation of PRX. These findings were confirmed in primary cultures of mesencephalic neurons and in rat brain injected stereotaxically. Overexpression of PRX1 in MN9D cells (MN9D/PRX1) exerted neuroprotective effects against death induced by 6-OHDA through scavenging of ROS. Consequently, generation of both superoxide anion and hydrogen peroxide following 6-OHDA treatment was decreased in MN9D/PRX1. Furthermore, overexpression of PRX1 protected cells against 6-OHDA-induced activation of p38 MAPK and subsequent activation of caspase-3. In contrast, 6-OHDA-induced apoptotic death signals were enhanced by RNA interference-targeted reduction of PRX1 in MN9D cells. Taken together, our data suggest that the redox state of PRX may be intimately involved in 6-OHDA-induced dopaminergic neuronal cell death and also provide a molecular mechanism by which PRX1 exerts a protective role in experimental models of Parkinson disease.
authors.affiliation: Department of Biology, 134 Shinchon-Dong, Seodaemoon-Gu, Yonsei University College of Science, Seoul, Korea.
authors.forename: Young Mook
authors.initials: YM
authors.lastname: Lee
authors.forename: Seong H
authors.initials: SH
authors.lastname: Park
authors.forename: Dong-Ik
authors.initials: DI
authors.lastname: Shin
authors.forename: Jee-Yeon
authors.initials: JY
authors.lastname: Hwang
authors.forename: Bokyung
authors.initials: B
authors.lastname: Park
authors.forename: Yun-Jong
authors.initials: YJ
authors.lastname: Park
authors.forename: Tae H
authors.initials: TH
authors.lastname: Lee
authors.forename: Ho Z
authors.initials: HZ
authors.lastname: Chae
authors.forename: Byung K
authors.initials: BK
authors.lastname: Jin
authors.forename: Tae H
authors.initials: TH
authors.lastname: Oh
authors.forename: Young J
authors.initials: YJ
authors.lastname: Oh
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D018663:Adrenergic Agents / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D002460:Cell Line; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D008636:Mesencephalon / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D016627:Oxidopamine / Q000633:toxicity*; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000378:metabolism*; D054464:Peroxiredoxins / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D018663:Adrenergic Agents; D017382:Reactive Oxygen Species; D016627:Oxidopamine; C489898:Prdx1 protein, rat; D054464:Peroxiredoxins; D048051:p38 Mitogen-Activated Protein Kinases; C505410:Casp3 protein, rat; D053148:Caspase 3; D000111:Acetylcysteine