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J. Biol. Chem., Vol. 283, Issue 15, 9986-9998, April 11, 2008

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Oxidative Modification of Peroxiredoxin Is Associated with Drug-induced Apoptotic Signaling in Experimental Models of Parkinson Disease^*

Young Mook Lee¹, Seong H. Park¹, Dong-Ik Shin¹, Jee-Yeon Hwang, BoKyung Park, Yun-Jong Park, Tae H. Lee, Ho Z. Chae, Byung K. Jin^¶, Tae H. Oh^||, and Young J. Oh²

From the Department of Biology, 134 Shinchon-Dong, Seodaemoon-Gu, Yonsei University College of Science, Seoul 120-749, Korea, the Department of Biological Science, Chonnam National University, Gwangju 500-757, Korea, the ^¶Brain Disease Research Center, Ajou University, Suwon, Korea, and the ^||Aging and Brain Diseases Research Center, KyungHee University, Seoul 130-701, Korea

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.

Received for publication, January 16, 2008 , and in revised form, February 4, 2008.

^* This work was supported by a grant from the Ministry of Science and Technology through the Brain Research Center (Infra-2) and in part by Ministry of Health and Welfare Grant A050874, Korea Science and Engineering Grant R01-2005-000-10179-0, Korean Research Foundation Grant KRF-C00204, and a Seoul R&D grant (to Y. J. O.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ These authors contributed equally to this work.

² To whom correspondence should be addressed. Fax: 82-2-312-5657; E-mail: yjoh{at}yonsei.ac.kr.

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