Copper chaperone for superoxide dismutase is essential to activate mammalian Cu/Zn superoxide dismutase
Copper chaperone for superoxide dismutase is essential to activate mammalian Cu/Zn superoxide dismutase
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DOI：
10.1073/pnas.040461197
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发表时间：
2000-03-14
影响因子：
11.1
通讯作者：
Gitlin, JD
中科院分区：
文献类型：
--
作者：
Wong, PC;Waggoner, D;Gitlin, JD
最近的研究表明，在酿酒酵母铜/锌超氧化物歧化酶（SOD 1）的交付是介导的胞质蛋白称为铜分子伴侣超氧化物歧化酶（CCS）。为了确定CCS在哺乳动物铜稳态中的作用，我们产生了具有CCS等位基因的靶向破坏的小鼠（CCS-/-小鼠）。尽管CCS-/-小鼠是存活的并且具有正常水平的SOD 1蛋白，但是当与对照同窝出生的小鼠相比时，它们显示SOD 1活性显著降低。用（CU）-C-64的代谢标记证明，CCS-/-小鼠中SOD 1活性的降低是Cu掺入SOD 1受损的直接结果，并且该效应是特异性的，因为在Cu摄取、分布、或掺入其它铜酶中。与这种SOD 1活性丧失相一致的是，CCS-/-小鼠表现出对百草枯的敏感性增加，雌性生育力降低，这些表型是SOD 1缺陷小鼠的特征。这些结果表明，任何哺乳动物铜分子伴侣的重要作用，并在家族性肌萎缩侧索硬化症的新的治疗策略的发展具有重要意义。
Recent studies in Saccharomyces cerevisiae suggest that the delivery of copper to Cu/Zn superoxide dismutase (SOD1) is mediated by a cytosolic protein termed the copper chaperone for superoxide dismutase (CCS). To determine the role of CCS in mammalian copper homeostasis, we generated mice with targeted disruption of CCS alleles (CCS-/- mice). Although CCS-/- mice are viable and possess normal levels of SOD1 protein, they reveal marked reductions in SOD1 activity when compared with control littermates, Metabolic labeling with (CU)-C-64 demonstrated that the reduction of SOD1 activity in CCS-/- mice is the direct result of impaired Cu incorporation into SOD1 and that this effect was specific because no abnormalities were observed in Cu uptake, distribution, or incorporation into other cuproenzymes. Consistent with this loss of SOD1 activity, CCS-/- mice showed increased sensitivity to paraquat and reduced female fertility, phenotypes that are characteristic of SOD1-deficient mice. These results demonstrate the essential role of any mammalian copper chaperone and have important implications for the development of novel therapeutic strategies in familial amyotrophic lateral sclerosis.