Parkin negatively regulates JNK pathway in the dopaminergic neurons of Drosophila
Parkin negatively regulates JNK pathway in the dopaminergic neurons of Drosophila
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DOI：
10.1073/pnas.0500346102
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发表时间：
2005-07-19
影响因子：
11.1
通讯作者：
Cho, KS
中科院分区：
文献类型：
--
作者：
Cha, GH;Kim, S;Cho, KS
Parkin是一种E3泛素连接酶，被发现与常染色体隐性青少年帕金森综合征有关，其主要特征是多巴胺能神经元的选择性丧失，随后出现运动缺陷。然而，这种神经元损失的分子机制仍然难以捉摸。在这里，我们的特点是果蝇帕金功能丧失突变体，表现出收缩的多巴胺能神经元酪氨酸羟化酶水平降低和受损的运动。通过给予L-DOPA，Parkin突变果蝇的行为缺陷得到部分恢复，并且Parkin突变果蝇脑中的多巴胺水平显著降低。有趣的是，我们发现c-Jun N-末端激酶（JNK）在帕金森突变体的多巴胺能神经元中被强烈激活，并且受损的多巴胺能神经元表型依赖于JNK信号通路的激活。与此一致，我们的上位性分析和哺乳动物细胞研究表明，帕金抑制JNK信号通路中的E3活性依赖性的方式。这些结果表明，帕金功能的损失上调JNK信号通路，这可能有助于在果蝇帕金突变体和常染色体隐性遗传的青少年帕金森综合征患者的多巴胺能神经元的脆弱性。
Parkin, an E3 ubiquitin ligase, has been found to be responsible for autosomal recessive juvenile parkinsonism characterized primarily by selective loss of dopaminergic neurons with subsequent defects in movements. However, the molecular mechanisms underlying this neuron loss remain elusive. Here, we characterized Drosophila parkin loss-of-function mutants, which exhibit shrinkage of dopaminergic neurons with decreased tyrosine hydroxylase level and impaired locomotion. The behavioral defect of parkin mutant flies was partially restored by administering L-DOPA, and the dopamine level in the brains of parkin mutant flies was highly decreased. Intriguingly, we found that c-Jun N-terminal kinase (JNK) is strongly activated in the dopaminergic neurons of parkin mutants and that impaired dopaminergic neuron phenotypes are dependent on the activation of the JNK signaling pathway. In consistent with this, our epistatic analysis and mammalian cell studies showed that Parkin inhibits the JNK signaling pathway in an E3 activity-dependent manner. These results suggest that loss of Parkin function up-regulates the JNK signaling pathway, which may contribute to the vulnerability of dopaminergic neurons in Drosophila parkin mutants and perhaps autosomal recessive juvenile parkinsonism patients.