JNK-mediated activation of ATF2 contributes to dopaminergic neurodegeneration in the MPTP mouse model of Parkinson's disease.
JNK-mediated activation of ATF2 contributes to dopaminergic neurodegeneration in the MPTP mouse model of Parkinson's disease.
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JNK 介导的 ATF2 激活导致帕金森病 MPTP 小鼠模型中的多巴胺能神经变性。
DOI：
10.1016/j.expneurol.2015.10.010
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发表时间：
2015
影响因子：
5.3
通讯作者：
Li Mingtao
中科院分区：
文献类型：
--
作者：
Huang Qiaoying;Du Xiaoxiao;He Xin;Yu Qing;Hu Kunhua;Breitwieser Wolfgang;Shen Qingyu;Ma Shanshan;Li Mingtao
c-Jun N-末端激酶（JNK）/c-Jun通路是帕金森病（PD）中多巴胺能神经元死亡的已知关键调节因子，并且被认为是神经保护治疗的潜在靶点。然而，JNK是否在多巴胺能神经元内被激活仍然存在争议，JNK是否通过c-Jun以外的下游效应器促进多巴胺能神经元死亡仍然不清楚。在这项研究中，我们证实，JNK，而不是p38激活多巴胺能神经元后，1-甲基-4-苯基-1，2，3，6-四氢吡啶（MPTP）中毒。此外，在MPTP处理的小鼠黑质的多巴胺能神经元内，JNK 2/3磷酸化激活转录因子2（ATF/CREB家族的转录因子）的苏氨酸69（Thr 69），而Thr 71的磷酸化是组成性的并且保持不变。在MPTP小鼠模型中，通过JNK在Thr 69上增加ATF 2的磷酸化表明了ATF 2的转录激活与多巴胺能神经元死亡之间的功能关系。通过使用多巴胺能神经元特异性条件性ATF 2突变小鼠，我们发现，无论是部分或完全删除的ATF 2 DNA结合结构域的多巴胺能神经元显着加剧MPTP诱导的多巴胺能神经元变性，表明激活的ATF 2在PD的神经发病机制中起着不利的作用。总之，我们的研究结果表明，JNK介导的ATF 2激活有助于多巴胺能神经元死亡的MPTP模型的PD。
The c-Jun N-terminal kinase (JNK)/c-Jun pathway is a known critical regulator of dopaminergic neuronal death in Parkinson's disease (PD) and is considered a potential target for neuroprotective therapy. However, whether JNK is activated within dopaminergic neurons remains controversial, and whether JNK acts through downstream effectors other than c-Jun to promote dopaminergic neuronal death remains unclear. In this study, we confirm that JNK but not p38 is activated in dopaminergic neurons after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-intoxication. Furthermore, within the dopaminergic neurons of the substantia nigra in MPTP-treated mice, JNK2/3 phosphorylates threonine 69 (Thr69) of Activating transcription factor-2 (ATF2), a transcription factor of the ATF/CREB family, whereas the phosphorylation of Thr71 is constitutive and remains unchanged. The increased phosphorylation of ATF2 on Thr69 by JNK in the MPTP mouse model suggests a functional relationship between the transcriptional activation of ATF2 and dopaminergic neuron death. By using dopaminergic neuron-specific conditional ATF2 mutant mice, we found that either partial or complete deletion of the ATF2 DNA-binding domain in dopaminergic neurons markedly alleviates the MPTP-induced dopaminergic neurodegeneration, indicating that the activation of ATF2 plays a detrimental role in neuropathogenesis in PD. Taken together, our findings demonstrate that JNK-mediated ATF2 activation contributes to dopaminergic neuronal death in an MPTP model of PD.