Mitochondrial dysfunction and increased sensitivity to excitotoxicity in mice deficient in DNA mismatch repair
Mitochondrial dysfunction and increased sensitivity to excitotoxicity in mice deficient in DNA mismatch repair
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DOI：
10.1111/j.1471-4159.2006.03864.x
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发表时间：
2006-07-01
影响因子：
4.7
通讯作者：
Memo, Maurizio
中科院分区：
文献类型：
--
作者：
Francisconi, Simona;Codenotti, Mara;Memo, Maurizio
分析了缺乏MutS同源基因（Msh 2）的一个等位基因的小鼠海马中的表达谱，该基因是DNA错配修复系统的最具代表性的组成部分之一，以了解修复缺陷或对DNA损伤的反应是否会显著影响脑功能。基因表达分析、生物化学和行为研究表明，总体结果表明线粒体功能降低。在Msh 2 +/-小鼠的海马中，通过RT-PCR和蛋白质印迹分析验证的阵列数据显示，细胞色素c氧化酶亚基2（CoxII）、ATP合成酶亚基β和超氧化物歧化酶1的基因表达水平降低。在生物化学上，这些小鼠海马和皮质的线粒体显示CoxII减少和乌头酸酶活性增加。在行为上，这些改变导致小鼠对红藻氨酸诱导的癫痫发作和海马神经元丢失的脆弱性增加。这些数据表明，缺乏一个有效的系统参与识别和修复DNA损伤可能会产生脑脊髓病。
The expression profile in the hippocampus of mice lacking one allele of the MutS homologue (Msh2), gene, which is one of the most representative components of the DNA mismatch repair system, was analysed to understand whether defects in the repair or in response to DNA damage could impact significantly on brain function. The overall results suggested a reduction in mitochondrial function as indicated by gene expression analysis, biochemical and behavioural studies. In the hippocampus of Msh2+/- mice, array data, validated by RT-PCR and western blot analysis, showed reduced expression levels of genes for cytochrome c oxidase subunit 2 (CoxII), ATP synthase subunit beta and superoxide dismutase 1. Biochemically, mitochondria from the hippocampus and cortex of these mice show reduced CoxII and increased aconitase activity. Behaviourally, these alterations resulted in mice with increased vulnerability to kainic acid-induced epileptic seizures and hippocampal neuronal loss. These data suggest that lack of an efficient system involved in recognizing and repairing DNA damage may generate a brain mitochondriopathy.