Involvement of double-stranded RNA-dependent protein kinase and phosphorylation of eukaryotic initiation factor-2α in neuronal degeneration
Involvement of double-stranded RNA-dependent protein kinase and phosphorylation of eukaryotic initiation factor-2α in neuronal degeneration
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DOI：
10.1046/j.1471-4159.2002.01237.x
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发表时间：
2002-12-01
影响因子：
4.7
通讯作者：
Hugon, J
中科院分区：
文献类型：
--
作者：
Chang, RCC;Suen, KC;Hugon, J
蛋白质翻译的抑制在细胞凋亡中起重要作用。虽然双链RNA依赖性蛋白激酶（PKR）被命名为通过病毒产生的双链RNA激活，但其激活通过真核起始因子2 α（eIF 2 α）的磷酸化诱导蛋白质翻译和凋亡的抑制。PKR也是一种应激激酶，其水平在衰老过程中增加。在这里，我们表明，PKR激活和eIF 2 α磷酸化在β-淀粉样蛋白（Abeta）肽，钙离子载体A23187和黄酮类化合物诱导的神经母细胞瘤细胞和原代神经元培养物的凋亡中起着重要作用。过度表达野生型PKR的神经母细胞瘤细胞暴露于Abeta肽中，eIF 2 α的磷酸化和凋亡细胞的数量增加，而显性阴性PKR减少了Abeta肽诱导的eIF 2 α磷酸化和凋亡。PKR敲除小鼠的原代培养神经元对Abeta肽毒性的敏感性也较低。由于细胞内钙螯合剂BAPTA-AM显著降低PKR磷酸化，因此通过A β肽激活PKR和eIF 2 α途径是由细胞内钙增加触发的。综上所述，这些结果表明PKR和eIF 2 α磷酸化可能参与导致神经元凋亡和死亡的分子信号事件，并可能成为神经保护的新靶点。
Inhibition of protein translation plays an important role in apoptosis. While double-stranded RNA-dependent protein kinase (PKR) is named as it is activated by double-stranded RNA produced by virus, its activation induces an inhibition of protein translation and apoptosis via the phosphorylation of the eukaryotic initiation factor 2alpha (eIF2alpha). PKR is also a stress kinase and its levels increase during ageing. Here we show that PKR activation and eIF2alpha phosphorylation play a significant role in apoptosis of neuroblastoma cells and primary neuronal cultures induced by the beta-amyloid (Abeta) peptides, the calcium ionophore A23187 and flavonoids. The phosphorylation of eIF2alpha and the number of apoptotic cells were enhanced in over-expressed wild-type PKR neuroblastoma cells exposed to Abeta peptide, while dominant-negative PKR reduced eIF2alpha phosphorylation and apoptosis induced by Abeta peptide. Primary cultured neurons from PKR knockout mice were also less sensitive to Abeta peptide toxicity. Activation of PKR and eIF2alpha pathway by Abeta peptide are triggered by an increase in intracellular calcium because the intracellular calcium chelator BAPTA-AM significantly reduced PKR phosphorylation. Taken together, these results reveal that PKR and eIF2alpha phosphorylation could be involved in the molecular signalling events leading to neuronal apoptosis and death and could be a new target in neuroprotection.