Temporal analysis of events associated with programmed cell death (apoptosis) of sympathetic neurons deprived of nerve growth factor.
Temporal analysis of events associated with programmed cell death (apoptosis) of sympathetic neurons deprived of nerve growth factor.
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DOI：
10.1083/jcb.123.5.1207
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发表时间：
1993-12
期刊：
影响因子：
--
通讯作者：
Johnson EM Jr
中科院分区：
文献类型：
--
作者：
Deckwerth TL;Johnson EM Jr
在培养的神经生长因子依赖的新生大鼠交感神经元中研究了神经生长因子（NGF）剥夺和神经保护后伴随变性和死亡的分子事件的时间过程，并与凋亡死亡进行了比较。NGF剥夺后12小时内，葡萄糖摄取，蛋白质合成和RNA合成急剧下降，其次是线粒体功能的中度下降。神经生长因子剥夺诱导的蛋白质合成减少和神经元死亡的分子机制进行了比较，发现是不同的，表明这种蛋白质合成的减少是不足以导致随后的死亡。在这些早期变化之后和神经元萎缩发作期间，蛋白质合成的抑制停止停止神经元变性，而再添加NGF或cAMP类似物保持神经保护6小时。这表明了一个模型，在这个模型中，一种假定的杀伤蛋白在神经元停止对NGF再注入的存活反应并开始死亡前几个小时达到致死水平。在5小时丧失活力并同时承诺死亡之前，神经元DNA片段化为寡核小体。DNA断裂的时间和药理学特征与DNA断裂是导致神经元死亡的机制的一部分一致。抗有丝分裂剂和神经毒素阿糖胞苷在NGF存在下诱导DNA片段化，支持先前的证据，即它密切模仿NGF剥夺诱导的死亡。因此，营养因子剥夺诱导的死亡是通过细胞凋亡发生的，是程序性细胞死亡的一个例子.
The time course of molecular events that accompany degeneration and death after nerve growth factor (NGF) deprivation and neuroprotection by NGF and other agents was examined in cultures of NGF-dependent neonatal rat sympathetic neurons and compared to death by apoptosis. Within 12 h after onset of NGF deprivation, glucose uptake, protein synthesis, and RNA synthesis fell precipitously followed by a moderate decrease of mitochondrial function. The molecular mechanisms underlying the NGF deprivation-induced decrease of protein synthesis and neuronal death were compared and found to be different, demonstrating that this decrease of protein synthesis is insufficient to cause death subsequently. After these early changes and during the onset of neuronal atrophy, inhibition of protein synthesis ceased to halt neuronal degeneration while readdition of NGF or a cAMP analogue remained neuroprotective for 6 h. This suggests a model in which a putative killer protein reaches lethal levels several hours before the neurons cease to respond to readdition of NGF with survival and become committed to die. Preceding loss of viability by 5 h and concurrent with commitment to die, the neuronal DNA fragmented into oligonucleosomes. The temporal and pharmacological characteristics of DNA fragmentation is consistent with DNA fragmentation being part of the mechanism that commits the neuron to die. The antimitotic and neurotoxin cytosine arabinoside induced DNA fragmentation in the presence of NGF, supporting previous evidence that it mimicked NGF deprivation-induced death closely. Thus trophic factor deprivation- induced death occurs by apoptosis and is an example of programmed cell death.