JNK3 mediates paraquat- and rotenone-induced dopaminergic neuron death.
JNK3 mediates paraquat- and rotenone-induced dopaminergic neuron death.
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DOI：
10.1097/nen.0b013e3181db8100
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发表时间：
2010-05
影响因子：
3.2
通讯作者：
Xia Z
中科院分区：
文献类型：
--
作者：
Choi WS;Abel G;Klintworth H;Flavell RA;Xia Z
多巴胺能神经元死亡的机制研究可能为帕金森病（PD）的治疗找到新的药物靶点。流行病学研究已将农药暴露与散发性帕金森病风险增加联系起来。在这里，我们研究了神经特异性JNK亚型c-Jun n -末端激酶3 （JNK3）在杀虫剂鱼藤酮和百草枯诱导的多巴胺能神经元死亡中的作用。通过RNA沉默和基因缺失来阻断JNK3信号传导，评估JNK3的作用。使用一种能够识别所有活化JNK亚型的抗体，我们发现百草枯和鱼藤酮可以刺激原代培养的多巴胺能神经元中JNK的磷酸化。在转染Jnk3特异性siRNA的培养神经元和Jnk3- / -小鼠神经元中，JNK的磷酸化几乎被消除，这表明Jnk3是这些杀虫剂在多巴胺能神经元中激活的主要JNK亚型。Jnk3 siRNA或Jnk3基因缺失也显著降低了百草枯和鱼藤酮诱导的多巴胺能神经元的死亡，在体内，Jnk3基因的缺失完全减弱了百草枯诱导的多巴胺能神经元的死亡和运动缺陷。我们的数据确定JNK3是百草枯和鱼藤酮诱导的多巴胺能神经元死亡的常见和关键介质，这表明它是PD治疗的潜在药物靶点。
Mechanistic studies underlying dopaminergic neuron death may identify new drug targets for the treatment of Parkinson disease (PD). Epidemiological studies have linked pesticide exposure to increased risk for sporadic PD. Here, we investigated the role of c-Jun N-terminal kinase 3 (JNK3), a neural-specific JNK isoform, in dopaminergic neuron death induced by the pesticides rotenone and paraquat. The role of JNK3 was evaluated using RNA silencing and gene deletion to block JNK3 signaling. Using an antibody that recognizes all isoforms of activated JNKs, we found that paraquat and rotenone stimulate JNK phosphorylation in primary cultured dopaminergic neurons. In cultured neurons transfected with Jnk3-specific siRNA and in neurons from Jnk3−/− mice, JNK phosphorylation was nearly abolished, suggesting that JNK3 is the main JNK isoform activated in dopaminergic neurons by these pesticides. Paraquat- and rotenone-induced death of dopaminergic neurons was also significantly reduced by Jnk3 siRNA or Jnk3 gene deletion and deletion of the Jnk3 gene completely attenuated paraquat-induced dopaminergic neuron death and motor-deficits in vivo. Our data identify JNK3 as a common and critical mediator of dopaminergic neuron death induced by paraquat and rotenone, suggesting that it is a potential drug target for PD treatment.