The herbicide paraquat induces dopaminergic nigral apoptosis through sustained activation of the JNK pathway

被引:167
作者
Peng, J
Mao, XO
Stevenson, FF
Hsu, M
Andersen, JK
机构
[1] Buck Inst Age Res, Novato, CA 94945 USA
[2] Univ So Calif, Dept Biol Sci, Program Mol Biol, Los Angeles, CA 90089 USA
关键词
D O I
10.1074/jbc.M404596200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:32626 / 32632
页数:7
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