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J. Biol. Chem., Vol. 279, Issue 11, 10710-10719, March 12, 2004

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Proteasome Mediates Dopaminergic Neuronal Degeneration, and Its Inhibition Causes -Synuclein Inclusions^*

Hideyuki Sawada, Ryuichi Kohno, Takeshi Kihara, Yasuhiko Izumi, Noriko Sakka, Masakazu Ibi, Miki Nakanishi, Tomoki Nakamizo, Kentarou Yamakawa, Hiroshi Shibasaki, Noriyuki Yamamoto, Akinori Akaike, Masatoshi Inden¶, Yoshihisa Kitamura¶, Takashi Taniguchi¶, and Shun Shimohama||

From the Department of Neurology, Graduate School of Medicine, 54 Shogoin-Kawaharacho, Sakyoku, Kyoto 606-8507, Japan, Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Shimoadachicho, Sakyoku, Kyoto 606-8501, Japan, and ^¶Department of Neurobiology, Kyoto Pharmaceutical University, Kyoto, Misasagi, Yamashinaku, Kyoto 607-8412, Japan

Parkinson's disease is characterized by dopaminergic neuronal death and the presence of Lewy bodies. -Synuclein is a major component of Lewy bodies, but the process of its accumulation and its relationship to dopaminergic neuronal death has not been resolved. Although the pathogenesis has not been clarified, mitochondrial complex I is suppressed, and caspase-3 is activated in the affected midbrain. Here we report that a combination of 1-methyl-4-phenylpyridinium ion (MPP⁺) or rotenone and proteasome inhibition causes the appearance of -synuclein-positive inclusion bodies. Unexpectedly, however, proteasome inhibition blocked MPP⁺- or rotenone-induced dopaminergic neuronal death. MPP⁺ elevated proteasome activity, dephosphorylated mitogen-activating protein kinase (MAPK), and activated caspase-3. Proteasome inhibition reversed the MAPK dephosphorylation and blocked caspase-3 activation; the neuroprotection was blocked by a p42 and p44 MAPK kinase inhibitor. Thus, the proteasome plays an important role in both inclusion body formation and dopaminergic neuronal death but these processes form opposite sides on the proteasome regulation in this model.

Received for publication, August 1, 2003 , and in revised form, December 10, 2003.

^* This work was supported by Grant-in-aid for Scientific Research (to H. S.) from Japan Society for the Promotion of Science 14570591 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.

The on-line version of this article (available at http://www.jbc.org) contains Supplemental Figs. 1-4.

^|| To whom correspondence should be addressed. Tel.: 81-75-751-3771; Fax: 81-75-751-3265; E-mail: i53367{at}sakura.kudpc.kyoto-u.ac.jp.

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