Constitutive overexpression of Cu/Zn superoxide dismutase exacerbates kainic acid-induced apoptosis of transgenic-Cu/Zn superoxide dismutase neurons
Constitutive overexpression of Cu/Zn superoxide dismutase exacerbates kainic acid-induced apoptosis of transgenic-Cu/Zn superoxide dismutase neurons
复制标题
DOI：
10.1073/pnas.93.16.8530
复制
发表时间：
1996-08-06
影响因子：
11.1
通讯作者：
Groner, Y
中科院分区：
文献类型：
--
作者：
BarPeled, O;Korkotian, E;Groner, Y
铜/锌超氧化物歧化酶（Cu/Zn SOD）是氧自由基代谢中的一种关键酶。该基因位于21号染色体上，在唐氏综合征患者中过度表达。利用转基因铜/锌超氧化物歧化酶（Tg - Cu/Zn SOD）小鼠中铜/锌超氧化物歧化酶活性升高的培养神经元，来确定铜/锌超氧化物歧化酶的组成性过度表达是否会产生一种内在的氧化应激，使Tg - Cu/Zn SOD神经元更易受到额外的损伤。来自三个独立衍生的Tg - Cu/Zn SOD品系的神经元比非转基因神经元对红藻氨酸（KA）介导的兴奋性毒性具有更高的敏感性，表现为更早发病和凋亡细胞死亡增加。转基因神经元对KA介导的凋亡的这种更高敏感性与一种慢性促氧化状态有关，这种状态表现为细胞内谷胱甘肽水平降低和[Ca2+]i稳态改变。这些数据与以下论点相符：铜/锌超氧化物歧化酶的过度表达在转基因神经元中产生慢性氧化应激，这加剧了它们对诸如KA介导的兴奋性毒性等额外损伤的敏感性。
Cu/Zn superoxide dismutase (Cu/Zn SOD) is a key enzyme in the metabolism of oxygen free radicals. The gene resides on chromosome 21 and is overexpressed in patients with Down syndrome. Cultured neurons of transgenic Cu/Zn SOD (Tg-Cu/Zn SOD) mice with elevated activity of Cu/Zn SOD were used to determine whether constitutive overexpression of Cu/Zn SOD creates an indigenous oxidative stress that predisposes the Tg-Cu/Zn SOD neurons to added insults. Neurons from three independently derived Tg-Cu/Zn SOD strains showed higher susceptibility than nontransgenic neurons to kainic acid (KA)-mediated excitotoxicity, reflected by an earlier onset and enhanced apoptotic cell death. This higher susceptibility of transgenic neurons to KA-mediated apoptosis was associated with a chronic prooxidant state that was manifested by reduced levels of cellular glutathione and altered [Ca2+](i) homeostasis. The data are compatible with the thesis that overexpression of Cu/Zn SOD creates chronic oxidative stress in the transgenic neurons, which exacerbates their susceptibility to additional insults such as KA-mediated excitotoxicity.