Bar-Peled O, Korkotian E, Segal M, Groner Y
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
Proc Natl Acad Sci U S A. 1996 Aug 6;93(16):8530-5. doi: 10.1073/pnas.93.16.8530.
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.
铜锌超氧化物歧化酶（Cu/Zn SOD）是氧自由基代谢中的关键酶。该基因位于21号染色体上，在唐氏综合征患者中过度表达。利用铜锌超氧化物歧化酶活性升高的转基因Cu/Zn SOD（Tg-Cu/Zn SOD）小鼠的培养神经元，来确定Cu/Zn SOD的组成型过表达是否会产生一种内源性氧化应激，使Tg-Cu/Zn SOD神经元更容易受到额外损伤。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）介导的兴奋性毒性更敏感，表现为发病更早且凋亡细胞死亡增加。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。这些数据与以下观点相符：Cu/Zn SOD的过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易感性。
