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J. Biol. Chem., Vol. 279, Issue 31, 32626-32632, July 30, 2004

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The Herbicide Paraquat Induces Dopaminergic Nigral Apoptosis through Sustained Activation of the JNK Pathway^*

Jun Peng, Xiao Ou Mao, Fang Feng Stevenson, Michael Hsu, and Julie K. Andersen¶

From the Buck Institute for Age Research, Novato, California 94945 and the Program in Molecular Biology, Department of Biological Sciences, University of Southern California, Los Angeles, California 90089

Environmental exposure to the oxidant-producing herbicide paraquat has been implicated as a risk factor in Parkinson's disease. Although intraperitoneal paraquat injections in mice cause a selective loss of dopaminergic neurons in the substantia nigra pars compacta, the exact mechanism involved is still poorly understood. Our data show that paraquat induces the sequential phosphorylation of c-Jun N-terminal kinase (JNK) and c-Jun and the activation of caspase-3 and sequential neuronal death both in vitro and in vivo. These effects are diminished by the specific JNK inhibitor SP600125 and the antioxidant manganese(III) tetrakis (4-benzoic acid) porphyrin in vitro. Furthermore, JNK pathway inhibitor CEP-11004 effectively blocks paraquat-induced dopaminergic neuronal death in vivo. These results suggest that the JNK signaling cascade is a direct activator of the paraquat-mediated nigral dopaminergic neuronal apoptotic machinery and provides a molecular linkage between oxidative stress and neuronal apoptosis.

Received for publication, April 26, 2004 , and in revised form, May 18, 2004.

^* This work was supported by National Institutes of Health Grant U54 ES12077 (to J. K. A). 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: Buck Institute for Age Research, 8001 Redwood Blvd., Novato, CA 94945. Tel.: 415-209-2070; Fax: 415-209-2231; E-mail: jandersen{at}buckinstitute.org.

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