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首页> 外文期刊>The European Journal of Neuroscience >MPP+-induced neuronal death in rats involves tyrosine 33 phosphorylation of WW domain-containing oxidoreductase WOX1.
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MPP+-induced neuronal death in rats involves tyrosine 33 phosphorylation of WW domain-containing oxidoreductase WOX1.

机译：MPP +诱导的大鼠神经元死亡涉及含WW域的氧化还原酶WOX1的酪氨酸33磷酸化。

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摘要

WW domain-containing oxidoreductase (named WWOX, FOR or WOX1) is a pro-apoptotic protein and tumor suppressor. Animals treated with dopaminergic neurotoxin 1-methyl-4-phenyl-pyridinium (MPP+) develop Parkinson's disease (PD)-like symptoms. Here we investigated whether WOX1 is involved in MPP+-induced neurodegeneration. Upon insult with MPP+ in rat brains, WOX1 protein was upregulated and phosphorylated at Tyr33 (or activated) in the injured neurons in the striatum and cortex ipsilaterally to intoxication, as determined by immunohistochemistry and Western blotting. Also, WOX1 was present in the condensed nuclei and damaged mitochondria of degenerative neurons, as revealed by transmission immunoelectron microscopy. Time-lapse microscopy revealed that MPP+ induced membrane blebbing and shrinkage of neuroblastoma SK-N-SH cells. Dominant-negative WOX1, a potent inhibitor of Tyr33 phosphorylation, abolished this event, indicating a critical role of the phosphorylation in apoptosis. c-Jun N-terminal kinase (JNK1) is known to bind and counteract the apoptotic function of WOX1. Suppression of JNK1 function by a dominant-negative spontaneously induced WOX1 activation. WOX1 physically interacted with JNK1 in SK-N-SH cells and rat brain extracts. MPP+ rapidly increased the binding, followed by dissociation, which is probably needed for WOX1 to exert apoptosis. We synthesized a short Tyr33-phosphorylated WOX1 peptide (11 amino acid residues). Interestingly, this peptide blocked MPP+-induced neuronal death in the rat brains, whereas non-phospho-WOX1 peptide had no effect. Together, activated WOX1 plays an essential role in the MPP+-induced neuronal death. Our synthetic phospho-WOX1 peptide prevents neuronal death, suggestive of its therapeutic potential in mitigating the symptoms of PD.
机译：含WW域的氧化还原酶（称为WWOX，FOR或WOX1）是促凋亡蛋白和肿瘤抑制因子。用多巴胺能神经毒素1-甲基-4-苯基-吡啶鎓（MPP +）治疗的动物会出现类似帕金森氏病（PD）的症状。在这里，我们调查了WOX1是否参与MPP +诱导的神经变性。通过免疫组织化学和Western印迹测定，在大鼠脑部受到MPP +损伤后，纹状体和皮层受损神经元的Tyr33上调WOX1蛋白并在Tyr33处磷酸化（或激活）。此外，如通过透射免疫电子显微镜所揭示的，WOX1存在于变性神经元的浓缩细胞核和线粒体受损中。延时显微镜显示，MPP +诱导了神经母细胞瘤SK-N-SH细胞的膜起泡和收缩。显性阴性WOX1，一种Tyr33磷酸化的有效抑制剂，废除了该事件，表明磷酸化在细胞凋亡中起着关键作用。已知c-Jun N末端激酶（JNK1）结合并抵消WOX1的凋亡功能。显性负自发性诱导WOX1激活抑制JNK1功能。 WOX1与SK-N-SH细胞和大鼠脑提取物中的JNK1物理相互作用。 MPP +会迅速增加结合，然后解离，这可能是WOX1发挥凋亡作用所必需的。我们合成了一个短的Tyr33磷酸化的WOX1肽（11个氨基酸残基）。有趣的是，该肽阻断了MPP +诱导的大鼠脑神经元死亡，而非磷酸化WOX1肽则没有作用。在一起，活化的WOX1在MPP +诱导的神经元死亡中起着至关重要的作用。我们的合成磷酸WOX1肽可防止神经元死亡，提示其在减轻PD症状方面的治疗潜力。

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