Targeted deletion of both thymidine phosphorylase and uridine phosphorylase and consequent disorders in mice
Targeted deletion of both thymidine phosphorylase and uridine phosphorylase and consequent disorders in mice
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DOI：
10.1128/mcb.22.14.5212-5221.2002
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发表时间：
2002-07-01
影响因子：
5.3
通讯作者：
Akiyama, S
中科院分区：
文献类型：
--
作者：
Haraguchi, M;Tsujimoto, H;Akiyama, S
胸腺嘧啶磷酸化酶（TP）调节细胞内和血浆胸腺嘧啶水平。TP缺乏被假设为：(i)血浆中胸苷水平升高，（ii）导致线粒体DNA改变，（iii）引起线粒体神经胃肠道脑肌病（MNGIE）。为了阐明TP的生理作用，我们培养了TP基因缺失的小鼠。虽然这些小鼠肝脏中的TP活性受到抑制，但在小肠中却完全维持。鼠尿苷磷酸化酶（UP），不像人的UP，裂解胸苷，以及尿苷。因此，我们产生了TP-UP双敲除（TP-/- UP-/-）小鼠。TP-/- UP-/-小鼠血清TP活性受到抑制，TP-/- UP-/-小鼠血浆胸苷水平高于TP-/-小鼠。出乎意料的是，即使给TP-/- UP-/-小鼠喂食胸苷7个月，我们也没有观察到TP-/- UP-/-小鼠的线粒体DNA改变或肌肉病理变化。然而，我们确实在TP-/- UP-/-小鼠的脑电镜研究中发现了磁共振T、脑图和轴突水肿的高强度病变。上述结果提示，TP活性的抑制可引起小鼠血浆嘧啶水平升高和脑轴突肿胀。由于大脑的病变似乎不是由于线粒体改变引起的，肌肉也没有发现病理变化，因此该模型将为MNGIE的病因提供进一步的见解。
Thymidine phosphorylase (TP) regulates intracellular and plasma thymidine levels. TP deficiency is hypothesized to (i) increase levels of thymidine in plasma, (ii) lead to mitochondrial DNA alterations, and (iii) cause mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). In order to elucidate the physiological roles of TP, we generated mice deficient in the TP gene. Although TP activity in the liver was inhibited in these mice, it was fully maintained in the small intestine. Murine uridine phosphorylase (UP), unlike human UP, cleaves thymidine, as well as uridine. We therefore generated TP-UP double-knockout (TP-/- UP-/-) mice. TP activities were inhibited in TP-/- UP-/- mice, and the level of thymidine in the plasma of TP-/- UP-/- mice was higher than for TP-/- mice. Unexpectedly, we could not observe alterations of mitochondrial DNA or pathological changes in the muscles of the TP-/- UP-/- mice, even when these mice were fed thymidine for 7 months. However, we did find hyperintense lesions on magnetic resonance T, maps in the brain and axonal edema by electron microscopic study of the brain in TP-/- UP-/- mice. These findings suggested that the inhibition of TP activity caused the elevation of pyrimidine levels in plasma and consequent axonal swelling in the brains of mice. Since lesions in the brain do not appear to be due to mitochondrial alterations and pathological changes in the muscle were not found, this model will provide further insights into the causes of MNGIE.