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J. Biol. Chem., Vol. 282, Issue 7, 4364-4372, February 16, 2007

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Proteasome Inhibition Induces Glutathione Synthesis and Protects Cells from Oxidative Stress

RELEVANCE TO PARKINSON DISEASE^*

Noriyuki Yamamoto, Hideyuki Sawada, Yasuhiko Izumi, Toshiaki Kume, Hiroshi Katsuki, Shun Shimohama^¶, and Akinori Akaike¹

From the Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, the Department of Neurology and Clinical Research Center, Center for Neurological Diseases, Utano National Hospital, 8 Ondoyama-cho, Narutaki, Ukyo-ku, Kyoto 616-5152, and the ^¶Department of Neurology, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan

The cause of selective dopaminergic neuronal degeneration in Parkinson disease has still not been resolved, but it has been hypothesized that oxidative stress and the ubiquitin-proteasome system are important in the pathogenesis. In this report, we investigated the effect of proteasome inhibition on oxidative stress-induced cytotoxicity in PC12 cells, an in vitro model of Parkinson disease. Treatment with proteasome inhibitors provided significant protection against toxicity by 6-hydroxydopamine and H₂O₂ in a concentration-dependent manner. The measurement of intracellular reactive oxygen species using 2',7'-dichlorofluorescein diacetate demonstrated that lactacystin, a proteasome inhibitor, significantly reduced 6-hydroxydopamineand H₂O₂-induced reactive oxygen species production. Proteasome inhibitors elevated the amount of glutathione and phosphorylated p38 mitogen-activated protein kinase (MAPK) prior to glutathione elevation. The treatment with lactacystin induced the nuclear translocation of NF-E2-related factor 2 (Nrf2) and increased the level of mRNA for -glutamylcysteine synthetase, a rate-limiting enzyme in glutathione synthesis. Furthermore, SB203580, an inhibitor of p38 MAPK, abolished glutathione elevation and cytoprotection by lactacystin. These data suggest that proteasome inhibition afforded cytoprotection against oxidative stress by the elevation of glutathione content, and its elevation was mediated by p38 MAPK phosphorylation.

Received for publication, April 18, 2006 , and in revised form, December 6, 2006.

^* This work was supported by grants-in-aid for Scientific Research from the Japan Society for the Promotion of Science and from the Ministry of Education, Culture, Sports, Science and Technology of Japan. 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 To whom correspondence should be addressed. Tel.: 81-75-753-4550; Fax: 81-75-753-4579; E-mail: aakaike{at}pharm.kyoto-u.ac.jp.

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