Differential involvement of cell cycle reactivation between striatal and cortical neurons in cell death induced by 3-nitropropionic acid
Differential involvement of cell cycle reactivation between striatal and cortical neurons in cell death induced by 3-nitropropionic acid
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DOI：
10.1074/jbc.m707730200
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发表时间：
2008-03-07
影响因子：
4.8
通讯作者：
Matsuki, Norio
中科院分区：
文献类型：
--
作者：
Akashiba, Hiroki;Ikegaya, Yuji;Matsuki, Norio
最近的证据表明，非计划的细胞周期活动会导致神经元细胞死亡。 3-硝基丙酸 (3-NP) 是琥珀酸脱氢酶的不可逆抑制剂，可诱导纹状体和大脑皮层细胞死亡。在这里，我们分析了异常细胞周期进程在这些大脑区域中 3-NP 诱导的细胞死亡中的参与情况。 3-NP 降低纹状体中细胞周期蛋白依赖性激酶抑制剂 p27 的水平，但不降低大脑皮层中的细胞周期蛋白依赖性激酶抑制剂 p27 的水平。 3-NP 还仅在纹状体中诱导视网膜母细胞瘤蛋白的磷酸化，这是 G(1) 期晚期细胞周期进展的标志物。药理学实验表明，细胞周期蛋白依赖性激酶活性和N-甲基-D-天冬氨酸（NMDA）受体协同参与纹状体神经元中3-NP引起的细胞死亡，而只有NMDA受体参与3-NP诱导的皮质神经元神经毒性。纹状体神经元死亡之前会出现体细胞 Ca2+ 升高和钙蛋白酶（一种 Ca2+ 依赖性蛋白酶）激活。 3-NP 引起的纹状体 p27 下调和细胞死亡均依赖于钙蛋白酶活性。此外，p27小干扰RNA的转染降低了纹状体细胞的活力。然而，在皮质神经元中，3-NP 并没有改变体细胞 Ca2+ 和钙蛋白酶活性，并且钙蛋白酶抑制剂没有保护作用。这些结果表明，3-NP 通过纹状体中的钙蛋白酶下调 p27 来诱导异常的细胞周期进程和神经元细胞死亡，但在大脑皮层中则不然。这是第一份关于细胞周期重新激活在不同大脑区域的差异参与的报告，并阐明了人类疾病（包括亨廷顿病）中区域选择性脆弱性的机制。
Recent evidence suggests that unscheduled cell cycle activity leads to neuronal cell death. 3-Nitropropionic acid (3-NP) is an irreversible inhibitor of succinate dehydrogenase and induces cell death in both striatum and cerebral cortex. Here we analyzed the involvement of aberrant cell cycle progression in 3-NP-induced cell death in these brain regions. 3-NP reduced the level of cyclin-dependent kinase inhibitor p27 in striatum but not in cerebral cortex. 3-NP also induced phosphorylation of retinoblastoma protein, a marker of cell cycle progression at late G(1) phase, only in striatum. Pharmacological experiments revealed that cyclin-dependent kinase activity and N-methyl-D-aspartate (NMDA) receptor were cooperatively involved in cell death by 3-NP in striatal neurons, whereas only NMDA receptor was involved in 3-NP-induced neurotoxicity in cortical neurons. Death of striatal neurons was preceded by elevation of somatic Ca2+ and activation of calpain, a Ca2+-dependent protease. Both striatal p27 down-regulation and cell death provoked by 3-NP were dependent on calpain activity. Moreover, transfection of p27 small interfering RNA reduced striatal cell viability. In cortical neurons, however, there was no change in somatic Ca2+ and calpain activity by 3-NP, and calpain inhibitors were not protective. These results suggest that 3-NP induces aberrant cell cycle progression and neuronal cell death via p27 down-regulation by calpain in striatum but not in the cerebral cortex. This is the first report for differential involvement of cell cycle reactivation in different brain regions and lightens the mechanism for region-selective vulnerability in human disease, including Huntington disease.