Oxidative modification of peroxiredoxin is associated with drug-induced apoptotic signaling in experimental models of Parkinson disease.
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.
Lee
Young Mook
YM
Department of Biology, 134 Shinchon-Dong, Seodaemoon-Gu, Yonsei University College of Science, Seoul, Korea.
Park
Seong H
SH
Shin
Dong-Ik
DI
Hwang
Jee-Yeon
JY
Park
Bokyung
B
Park
Yun-Jong
YJ
Lee
Tae H
TH
Chae
Ho Z
HZ
Jin
Byung K
BK
Oh
Tae H
TH
Oh
Young J
YJ
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
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