Dramatic phenotypic improvement during pregnancy in a genetic leukodystrophy: estrogen appears to be a critical factor.
Dramatic phenotypic improvement during pregnancy in a genetic leukodystrophy: estrogen appears to be a critical factor.
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遗传性脑白质营养不良在妊娠期间表型显着改善：雌激素似乎是一个关键因素。
DOI：
10.1093/hmg/10.23.2709
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发表时间：
2001
影响因子：
3.5
通讯作者：
Suzuki,K
中科院分区：
文献类型：
--
作者：
Matsuda,J;Vanier,MT;Saito,Y;Suzuki,K;Suzuki,K
球样细胞脑白质营养不良是人类经典的遗传性脑白质营养不良之一。人类典型的婴儿疾病（克拉伯病）是由溶酶体半乳糖神经酰胺酶缺乏引起的。我们最近通过灭活saposin A（半乳糖神经酰胺酶的基本激活剂），产生了一种新的迟发性慢性形式的疾病小鼠模型。saposin A-/-小鼠的表型特征在性质上与twitcher小鼠相同，但较twitcher小鼠温和，这是由遗传性半乳糖神经酰胺酶缺乏引起的。在saposin A-/-小鼠的交叉过程中，我们观察到，与未经历怀孕的受影响雌性或受影响雄性相比，持续怀孕的受影响雌性显示出极大改善的神经系统症状。球样细胞脑白质营养不良的病理标志，脱髓鞘伴球样细胞浸润，基本消失。妊娠saposin A-/-小鼠脑内免疫相关基因（MCP-1、TNF-α）表达显著下调。此外，我们还发现saposin A-/-小鼠脱髓鞘区的球状细胞、活化的星形胶质细胞和小胶质细胞上雌激素受体（ERα和ERβ）的强表达。当saposin A-/-小鼠皮下植入30至90天的缓释17β-雌二醇（E2）颗粒时，病理学得到极大改善。这些发现表明，怀孕期间较高的雌激素水平是怀孕保护作用的重要因素之一。虽然我们在将小鼠的这些观察结果外推到人类疾病时应该谨慎，但这种现象非常引人注目，雌激素给药可能值得考虑作为某些慢性遗传性脑白质营养不良的补充治疗。
Globoid cell leukodystrophy is one of the classical genetic leukodystrophies in humans. The typical infantile disease in man (Krabbe disease) is caused by deficiency of lysosomal galactosylceramidase. We recently generated a new mouse model of a late-onset, chronic form of the disease by inactivating saposin A, the essential activator of galactosylceramidase. The phenotypic features of saposin A–/–mice are qualitatively identical but milder than those oftwitchermice, which is caused by genetic galactosylceramidase deficiency. During intercrossing of saposin A–/–mice, we observed that affected females that are continually pregnant showed greatly improved neurological symptoms compared to affected females that do not experience pregnancy, or affected males. The pathological hallmark of globoid cell leukodystrophy, demyelination with infiltration of globoid cells, largely disappeared. The immune-related gene expression (MCP-1, TNF-α) was significantly down-regulated in the brain of pregnant saposin A–/–mice. In addition, we found intense expression of the estrogen receptors (ERα and ERβ) on the globoid cells, activated astrocytes and microglia in the demyelinating area of saposin A–/–mice. When saposin A–/–mice were subcutaneously implanted with time-release 17β-estradiol (E2) pellets from 30 to 90 days, the pathology was vastly improved. These findings suggest that a higher level of estrogen during pregnancy is one of the important factors in the protective effect of pregnancy. While we should be cautious in extrapolating these observations in the mouse to human disease, the phenomenon is spectacularly dramatic and estrogen administration might be worth a consideration as a supplementary treatment for some chronic genetic leukodystrophies.