Oxidative stress triggers neuronal caspase-independent death: Endonuclease G involvement in programmed cell death-type III
Oxidative stress triggers neuronal caspase-independent death: Endonuclease G involvement in programmed cell death-type III
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DOI：
10.1007/s00018-009-0079-2
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发表时间：
2009-08-01
影响因子：
8
通讯作者：
Nagley, Phillip
中科院分区：
文献类型：
--
作者：
Higgins, Gavin C.;Beart, Philip M.;Nagley, Phillip
为了表征神经元死亡，将原代皮质神经元（C57/Black 6 J小鼠）暴露于过氧化氢（H2 O2）和星形孢菌素。两者都引起细胞收缩、核浓缩、DNA片段化和质膜完整性丧失。两种处理均未诱导caspase-7活性，但caspase-3被星形孢菌素激活，但不被H2 O2激活。每次处理引起核酸内切酶G（Endo G）和细胞色素c从线粒体的再分配。使用siRNA敲低Endo G表达的神经元在用H2 O2处理后显示出核凝聚和DNA片段化的减少，但不是星形孢菌素。Endo G抑制保护细胞免受H2 O2诱导的细胞死亡，而staurosporine诱导的死亡仅被延迟。我们得出结论，星形孢菌素诱导这些神经元的凋亡，但严重的氧化应激导致内G依赖性死亡，在没有半胱天冬酶激活（程序性细胞死亡III型）。因此，氧化应激在神经元中触发一种形式的坏死，这是一种受分子调节的系统性细胞反应。
To characterize neuronal death, primary cortical neurons (C57/Black 6 J mice) were exposed to hydrogen peroxide (H2O2) and staurosporine. Both caused cell shrinkage, nuclear condensation, DNA fragmentation and loss of plasma membrane integrity. Neither treatment induced caspase-7 activity, but caspase-3 was activated by staurosporine but not H2O2. Each treatment caused redistribution from mitochondria of both endonuclease G (Endo G) and cytochrome c. Neurons knocked down for Endo G expression using siRNA showed reduction in both nuclear condensation and DNA fragmentation after treatment with H2O2, but not staurosporine. Endo G suppression protected cells against H2O2-induced cell death, while staurosporine-induced death was merely delayed. We conclude that staurosporine induces apoptosis in these neurons, but severe oxidative stress leads to Endo G-dependent death, in the absence of caspase activation (programmed cell death-type III). Therefore, oxidative stress triggers in neurons a form of necrosis that is a systematic cellular response subject to molecular regulation.