ALS-linked Cu/Zn-SOD mutation increases vulnerability of motor neurons to excitotoxicity by a mechanism involving increased oxidative stress and perturbed calcium homeostasis
ALS-linked Cu/Zn-SOD mutation increases vulnerability of motor neurons to excitotoxicity by a mechanism involving increased oxidative stress and perturbed calcium homeostasis
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DOI：
10.1006/exnr.1999.7190
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发表时间：
1999-11-01
影响因子：
5.3
通讯作者：
Mattson, MP
中科院分区：
文献类型：
--
作者：
Kruman, II;Pedersen, WA;Mattson, MP
我们采用ALS小鼠模型，其中家族性ALS连锁的Cu/Zn-SOD突变的过度表达导致进行性MN损失和与人类ALS患者的临床表型显著相似的临床表型，以直接测试ALS的兴奋毒性假说。在基础培养条件下，MN在混合脊髓培养的Cu/Zn-SOD突变小鼠表现出增强的氧自由基的产生，脂质过氧化，增加细胞内钙水平，降低线粒体内钙水平，和线粒体功能障碍。来自Cu/Zn-SOD突变小鼠的MN表现出对由α-氨基-3-羟基-5-甲基异恶唑-4-丙酸酯受体介导的谷氨酸毒性的极大增加的脆弱性。从Cu/Zn-SOD突变小鼠的MN谷氨酸毒性的脆弱性增加与增强的氧自由基的产生，持续升高的细胞内钙水平，和线粒体功能障碍。预处理的文化与维生素E，一氧化氮抑制剂，过氧亚硝酸清除剂，和雌激素保护MN从Cu/Zn-SOD突变小鼠对兴奋性毒性。Cu/Zn-SOD突变小鼠脊髓MNs的兴奋性毒素诱导的变性比野生型小鼠更广泛。与Cu/Zn-SOD突变相关的线粒体功能障碍可能在干扰钙稳态和增加氧自由基产生中起重要作用，从而增加MN对兴奋性毒性的脆弱性，（C）1999学术出版社。
We employed a mouse model of ALS, in which overexpression of a familial ALS-linked Cu/Zn-SOD mutation leads to progressive MN loss and a clinical phenotype remarkably similar to that of human ALS patients, to directly test the excitotoxicity hypothesis of ALS. Under basal culture conditions, MNs in mixed spinal cord cultures from the Cu/Zn-SOD mutant mice exhibited enhanced oxyradical production, lipid peroxidation, increased intracellular calcium levels, decreased intramitochondrial calcium levels, and mitochondrial dysfunction. MNs from the Cu/Zn-SOD mutant mice exhibited greatly increased vulnerability to glutamate toxicity mediated by alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate receptors. The increased vulnerability of MNs from Cu/Zn-SOD mutant mice to glutamate toxicity was associated with enhanced oxyradical production, sustained elevations of intracellular calcium levels, and mitochondrial dysfunction. Pretreatment of cultures with vitamin E, nitric oxide-suppressing agents, peroxynitrite scavengers, and estrogen protected MNs from Cu/Zn-SOD mutant mice against excitotoxicity. Excitotoxin-induced degeneration of spinal cord MNs in adult mice was more extensive in Cu/Zn-SOD mutant mice than in wild-type mice. The mitochondrial dysfunction associated with Cu/Zn-SOD mutations may play an important role in disturbing calcium homeostasis and increasing oxyradical production, thereby increasing the vulnerability of MNs to excitotoxicity, (C) 1999 Academic Press.