Small peptide inhibitor of JNKs protects against MPTP-induced nigral dopaminergic injury via inhibiting the JNK-signaling pathway
Small peptide inhibitor of JNKs protects against MPTP-induced nigral dopaminergic injury via inhibiting the JNK-signaling pathway
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JNK 的小肽抑制剂通过抑制 JNK 信号通路来防止 MPTP 诱导的黑质多巴胺能损伤
DOI：
10.1038/labinvest.2009.124
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发表时间：
2009-12
影响因子：
5
通讯作者：
陈生弟
中科院分区：
文献类型：
--
作者：
陈生弟
越来越多的证据表明，细胞凋亡可能是帕金森病（PD）中黑质多巴胺能神经元选择性丧失的潜在细胞死亡机制。以往的研究表明c-Jun N-末端激酶（JNK）信号通路在1-甲基-4-苯基-1，2，3，6-四氢吡啶（MPTP）诱导的PD动物模型中具有重要作用。在这项研究中，我们报告的抑制作用的肽命名为Tat-JBD对JNKs激活。达特的序列对应于人类免疫缺陷病毒1型（HIV-1）的细胞膜转导结构域，11个氨基酸的肽序列对应于JNK相互作用蛋白-1（JIP-1）上JNK结合结构域（JBD）的残基。Tat-JBD能干扰JIP-1-JNKs复合物的组装，抑制MPTP诱导的JNKs活化，从而减少c-Jun的磷酸化，抑制Bcl-2的磷酸化，抑制Bax从Bcl-2/Bax二聚体中的释放，进而减少Bax向线粒体的转位，细胞色素c的释放，半胱天冬酶3的激活和聚ADP核糖聚合酶的水解。多巴胺能神经元的死亡和纹状体多巴胺能轴突的损失显着抑制肽Tat-JBD在MPTP处理的小鼠的输注。我们的研究结果表明，Tat-JBD通过抑制JNK信号通路对MPTP损伤提供神经保护，并可能为PD提供有希望的治疗方法。
Increasing evidence suggests that apoptosis may be the mechanism underlying cell death in selective loss of nigral dopaminergic neurons in Parkinson's disease (PD). Previous studies strongly suggested that c-Jun N-terminal kinase (JNK) signaling pathway has a critical role in the animal model with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD. In this study, we report the inhibitory effect of a peptide designated as Tat-JBD on JNKs activation. The sequence of Tat is corresponding to the cell-membrane transduction domain of human immunodeficiency virus-type 1 (HIV-1) and the sequence of an 11-amino acid peptide is corresponding to the residues of JNK-binding domain (JBD) on JNK-interacting protein-1 (JIP-1). Tat-JBD is confirmed to perturb the assembly of JIP-1-JNKs complex, inhibit the activation of JNKs induced by MPTP and consequently diminish the phosphorylation of c-Jun. It also inhibits the phosphorylation of Bcl-2 and the releasing of Bax from Bcl-2/Bax dimmers, sequentially attenuates the translocation of Bax to mitochondria, the release of cytochrome c, the activation of caspase3 and the hydrolyzation of poly-ADP-ribose-polymerase. The death of dopaminergic neurons and the loss of dopaminergic axon in the striatum were significantly suppressed by infusion of the peptide Tat-JBD in MPTP-treated mice. Our findings imply that Tat-JBD offers neuroprotection against MPTP injury via inhibiting the JNK-signaling pathway, and may provide a promising therapeutic approach for PD.
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影响因子：
2.5
作者：
Jing-kun Pan;D. Pei;Xiao-hui Yin;Liang Hui;Guang-yi Zhang
通讯作者：
Jing-kun Pan;D. Pei;Xiao-hui Yin;Liang Hui;Guang-yi Zhang
影响因子：
16.2
作者：
Becker, EBE;Bonni, A
通讯作者：
Bonni, A
影响因子：
3.6
作者：
Pan, Jing;Wang, Gang;Chen, Sheng-Di
通讯作者：
Chen, Sheng-Di
影响因子：
5.3
作者：
Zhang, Quan-Guang;Wang, Ruimin;Khan, Mohammad;Mahesh, Virendra;Brann, Darrell W.
通讯作者：
Brann, Darrell W.
DOI：
10.1073/pnas.0501600102
发表时间：
2005-10-04
影响因子：
11.1
作者：
Kim, JW;Kim, MJ;Choi, EJ
通讯作者：
Choi, EJ