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Originally published In Press as doi:10.1074/jbc.M311164200 on March 1, 2004
J. Biol. Chem., Vol. 279, Issue 19, 20451-20460, May 7, 2004
Phosphorylation of p38 MAPK Induced by Oxidative Stress Is Linked to Activation of Both Caspase-8- and -9-mediated Apoptotic Pathways in Dopaminergic Neurons*
Won-Seok Choi ,
Dae-Seok Eom,
Baek S. Han,
Won K. Kim ,
Byung H. Han¶,
Eui-Ju Choi||,
Tae H. Oh**,
George J. Markelonis**,
Jin W. Cho, and
Young J. Oh
From the
Department of Biology and Protein Network Research Center, Yonsei University College of Science, Seoul 120-749, the Department of Pharmacology, Ewha Woman's University School of Medicine, Seoul 110-783, ¶Natural Products Research Institute, Seoul National University College of Pharmacy, Seoul 110-460, ||Graduate School of Biotechnology, Korea University, Seoul 136-701, Korea, and the **Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, Maryland 21201
We evaluated the contribution of p38 mitogen-activated protein kinase and the events upstream/downstream of p38 leading to dopaminergic neuronal death. We utilized MN9D cells and primary cultures of mesencephalic neurons treated with 6-hydroxydopamine. Phosphorylation of p38 preceded apoptosis and was sustained in 6-hydroxydopamine-treated MN9D cells. Co-treatment with PD169316 (an inhibitor of p38) or expression of a dominant negative p38 was neuroprotective in death induced by 6-hydroxydopamine. The superoxide dismutase mimetic and the nitric oxide chelator blocked 6-hydroxydopamine-induced phosphorylation of p38, suggesting a role for superoxide anion and nitric oxide in eliciting a neurotoxic signal by activating p38. Following 6-hydroxydopamine treatment, inhibition of p38 prevented both caspase-8- and -9-mediated apoptotic pathways as well as generation of truncated Bid. Consequently, 6-hydroxydopamine-induced cell death was rescued by blockading activation of caspase-8 and -9. In primary cultures of mesencephalic neurons, the phosphorylation of p38 similarly appeared in tyrosine hydroxylase-positive, dopaminergic neurons after 6-hydroxydopamine treatment. This neurotoxin-induced phosphorylation of p38 was inhibited in the presence of superoxide dismutase mimetic or nitric oxide chelator. Co-treatment with PD169316 deterred 6-hydroxydopamine-induced loss of dopaminergic neurons and activation of caspase-3 in these neurons. Furthermore, inhibition of caspase-8 and -9 significantly rescued 6-hydroxydopamine-induced loss of dopaminergic neurons. Taken together, our data suggest that superoxide anion and nitric oxide induced by 6-hydroxydopamine initiate the p38 signal pathway leading to activation of both mitochondrial and extramitochondrial apoptotic pathways in our culture models of Parkinson's disease.
Received for publication, October 10, 2003
, and in revised form, February 27, 2004.
* This work was supported by Korea Research Foundation Grant E00109, in part by the Ministry of Health and Welfare Grant 03-PJ1-PG10-21300-0023, the KOSEF through the Brain Research Center at Ajou University, the Ministry of Science and Technology Grants M1-0108-00-0096, FPR-02-A-1, and NM-2-44 (to Y. J. O.), and a postdoctoral grant from Yonsei Center for Biotechnology (to W.-S. C.). 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.
To whom correspondence should be addressed: Dept. of Biology, Yonsei University College of Science, 134 Shinchon-Dong, Seodaemoon-Gu, Seoul 120-749, Korea. Tel.: 82-2-2123-2662; Fax: 82-2-312-5657; E-mail: yjoh{at}yonsei.ac.kr.
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Copyright © 2004 by the American Society for Biochemistry and Molecular Biology.
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