Matsuda J, Vanier M T, Saito Y, Suzuki K, Suzuki K
Neuroscience Center, University of North Carolina, Chapel Hill, NC 27599-7250, USA.
Hum Mol Genet. 2001 Nov 1;10(23):2709-15. doi: 10.1093/hmg/10.23.2709.
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 of twitcher mice, 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-alpha) was significantly down-regulated in the brain of pregnant saposin A(-/-) mice. In addition, we found intense expression of the estrogen receptors (ER alpha and ER beta) 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 17 beta-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.
球形细胞脑白质营养不良是人类典型的遗传性脑白质营养不良之一。人类典型的婴儿型疾病（克拉伯病）是由溶酶体半乳糖神经酰胺酶缺乏引起的。我们最近通过使半乳糖神经酰胺酶的必需激活剂鞘脂激活蛋白A失活，建立了一种迟发性、慢性形式疾病的新小鼠模型。鞘脂激活蛋白A基因敲除小鼠的表型特征在性质上与因遗传性半乳糖神经酰胺酶缺乏导致的震颤小鼠相同，但症状较轻。在鞘脂激活蛋白A基因敲除小鼠的杂交过程中，我们观察到持续怀孕的患病雌性小鼠与未怀孕的患病雌性小鼠或患病雄性小鼠相比，神经症状有了显著改善。球形细胞脑白质营养不良的病理特征，即伴有球形细胞浸润的脱髓鞘病变，在很大程度上消失了。怀孕的鞘脂激活蛋白A基因敲除小鼠大脑中与免疫相关的基因表达（单核细胞趋化蛋白-1、肿瘤坏死因子-α）显著下调。此外，我们发现鞘脂激活蛋白A基因敲除小鼠脱髓鞘区域的球形细胞、活化的星形胶质细胞和小胶质细胞上有强烈的雌激素受体（雌激素受体α和雌激素受体β）表达。当在30至90天给鞘脂激活蛋白A基因敲除小鼠皮下植入缓释17β-雌二醇（E2）微丸时，病理状况得到了极大改善。这些发现表明，怀孕期间较高水平的雌激素是怀孕起到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至人类疾病时应谨慎，但这种现象非常显著，雌激素给药可能值得作为某些慢性遗传性脑白质营养不良的辅助治疗方法加以考虑。
