JNK inhibition of VMAT2 contributes to rotenone-induced oxidative stress and dopamine neuron death.
JNK inhibition of VMAT2 contributes to rotenone-induced oxidative stress and dopamine neuron death.
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DOI：
10.1016/j.tox.2014.12.005
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发表时间：
2015-02-03
期刊：
影响因子：
4.5
通讯作者：
Xia, Zhengui
中科院分区：
文献类型：
--
作者：
Choi, Won-Seok;Kim, Hyung-Wook;Xia, Zhengui
鱼藤酮治疗，无论是体外还是体内，都被广泛用于模拟暴露于环境神经毒物和杀虫剂后帕金森病多巴胺神经元死亡。鱼藤酮神经毒性的机制仍在研究中。我们最近的研究表明，鱼藤酮诱导的多巴胺神经元死亡涉及微管不稳定，这导致细胞质多巴胺和活性氧（ROS）的积累。此外，c-Jun n端蛋白激酶（JNK）是鱼藤酮诱导的多巴胺神经元死亡所必需的。在这里，我们报告了JNKs的神经特异性JNK3亚型，而不是JNK1或JNK2，在原代培养的多巴胺神经元中负责这种神经元死亡。紫杉醇是一种微管稳定剂，可以减弱鱼藤酮诱导的磷酸化和JNK的激活。这表明JNK在鱼藤酮暴露后被微管不稳定激活。此外，鱼藤酮抑制VMAT2活性，但不抑制VMAT2蛋白水平。值得注意的是，用JNKs的药理学抑制剂SP600125治疗可以减弱鱼烯酮对VMAT2的抑制作用。此外，重组JNK3蛋白与纯化的中脑突触囊泡体外孵育后，VMAT2活性降低，表明JNK3可以抑制VMAT2活性。结合我们之前的研究结果，这些结果表明鱼藤酮通过一系列连续事件诱导多巴胺神经元死亡，包括微管不稳定、JNK3激活、VMAT2抑制、胞质多巴胺积累和ROS的产生。我们的数据表明JNK3是一种新的VMAT2活性调节因子。
Treatment with rotenone, both in vitro and in vivo, is widely used to model dopamine neuron death in Parkinson’s disease upon exposure to environmental neurotoxicants and pesticides. Mechanisms underlying rotenone neurotoxicity are still being defined. Our recent studies suggest that rotenone-induced dopamine neuron death involves microtubule destabilization, which leads to accumulation of cytosolic dopamine and consequently reactive oxygen species (ROS). Furthermore, the c-Jun N-terminal protein kinase (JNK) is required for rotenone-induced dopamine neuron death. Here we report that the neural specific JNK3 isoform of the JNKs, but not JNK1 or JNK2, is responsible for this neuron death in primary cultured dopamine neurons. Treatment with taxol, a microtubule stabilizing agent, attenuates rotenone-induced phosphorylation and presumably activation of JNK. This suggests that JNK is activated by microtubule destabilization upon rotenone exposure. Moreover, rotenone inhibits VMAT2 activity but not VMAT2 protein levels. Significantly, treatment with SP600125, a pharmacological inhibitor of JNKs, attenuates rotenone inhibition of VMAT2. Furthermore, decreased VMAT2 activity following in vitro incubation of recombinant JNK3 protein with purified mesencephalic synaptic vesicles suggests that JNK3 can inhibit VMAT2 activity. Together with our previous findings, these results suggest that rotenone induces dopamine neuron death through a series of sequential events including microtubule destabilization, JNK3 activation, VMAT2 inhibition, accumulation of cytosolic dopamine, and generation of ROS. Our data identify JNK3 as a novel regulator of VMAT2 activity.
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DOI：
10.1097/nen.0b013e3181db8100
发表时间：
2010-05
影响因子：
3.2
作者：
Choi WS;Abel G;Klintworth H;Flavell RA;Xia Z
通讯作者：
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DOI：
10.1007/978-1-61779-170-3_19
发表时间：
2011
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
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作者：
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DOI：
10.1007/978-1-62703-444-9_6
发表时间：
2013-01-01
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
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作者：
Choi, Won-Seok;Kim, Hyung-Wook;Xia, Zhengui
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影响因子：
3.7
作者：
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影响因子：
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作者：
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通讯作者：
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