A MAPK/c-Jun-mediated switch regulates the initial adaptive and cell death responses to mitochondrial damage in a neuronal cell model.
A MAPK/c-Jun-mediated switch regulates the initial adaptive and cell death responses to mitochondrial damage in a neuronal cell model.
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MAPK/c-Jun 介导的开关调节神经元细胞模型中线粒体损伤的初始适应性和细胞死亡反应。
DOI：
10.1016/j.biocel.2018.09.008
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Ryan TA
中科院分区：
文献类型：
--
作者：
Ryan TA
帕金森氏病（PD）的定义是多巴胺能神经元的进行性丧失。线粒体功能障碍和氧化应激与PD相关，尽管神经元如何响应这些应激尚不完全清楚。适应性和凋亡神经元应激反应途径如何调节以及它们被激活的阈值仍然不清楚。利用SH-SY 5 Y神经母细胞瘤细胞，我们表明，MAPK/AP-1途径是至关重要的，在调节线粒体解偶联的反应。在这里，我们发现AP-1转录因子c-Jun可以以促凋亡或抗凋亡的方式起作用，这取决于应激水平。JNK介导的分化细胞中的细胞死亡仅在超过应激阈值时发生。我们还确定了一个新的反馈回路之间的帕金活动和c-Jun的反应，这表明有缺陷的线粒体自噬可能会启动MAPK/c-Jun介导的神经元损失观察PD。我们的数据支持这样的假设，即阻断c-Jun上游的细胞死亡途径作为PD的治疗靶点可能是不合适的，因为促凋亡和抗凋亡反应交叉。因此，增强适应性反应或靶向神经元死亡反应的特定方面可能代表更可行的治疗策略。
Parkinson’s disease (PD) is defined by the progressive loss of dopaminergic neurons. Mitochondrial dysfunction and oxidative stress are associated with PD although it is not fully understood how neurons respond to these stresses. How adaptive and apoptotic neuronal stress response pathways are regulated and the thresholds at which they are activated remains ambiguous. Utilising SH-SY5Y neuroblastoma cells, we show that MAPK/AP-1 pathways are critical in regulating the response to mitochondrial uncoupling. Here we found the AP-1 transcription factor c-Jun can act in either a pro- or anti-apoptotic manner, depending on the level of stress. JNK-mediated cell death in differentiated cells only occurred once a threshold of stress was surpassed. We also identified a novel feedback loop between Parkin activity and the c-Jun response, suggesting defective mitophagy may initiate MAPK/c-Jun-mediated neuronal loss observed in PD. Our data supports the hypothesis that blocking cell death pathways upstream of c-Jun as a therapeutic target in PD may not be appropriate due to crossover of the pro- and anti-apoptotic responses. Boosting adaptive responses or targeting specific aspects of the neuronal death response may therefore represent more viable therapeutic strategies.
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DOI：
10.1083/jcb.200910140
发表时间：
2010-04-19
期刊：
The Journal of cell biology
影响因子：
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