Establishment of immortalized Schwann cells from Fabry mice and their low uptake of recombinant α-galactosidase
Establishment of immortalized Schwann cells from Fabry mice and their low uptake of recombinant α-galactosidase
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DOI：
10.1007/s10038-007-0210-x
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发表时间：
2007-12-01
影响因子：
3.5
通讯作者：
Sakuraba, Hitoshi
中科院分区：
文献类型：
--
作者：
Kawashima, Ikuo;Watabe, Kazuhiko;Sakuraba, Hitoshi
周围神经病变是Fabry病的重要表现之一。目前可用的重组α-半乳糖苷酶的酶替代疗法并不总是改善法布里病神经病变。但原因尚未确定。我们建立了一个Schwann细胞系Fabry小鼠，其特征在于，然后检查细胞的α-半乳糖苷酶的摄取和其对积累的底物的降解的影响。细胞表现出独特的许旺细胞形态和生化表型（α-半乳糖苷酶活性缺乏，细胞中存在大量细胞质包涵体）。将添加到培养基中的重组α-半乳糖苷酶以剂量依赖性方式掺入培养的Fabry Schwann细胞中。但细胞相关酶活性的增加低于人类和小鼠Fabry成纤维细胞的情况。给予高剂量的酶改善了细胞的病理变化，尽管低剂量的酶没有改善。在甘露糖6-磷酸存在下，酶的细胞摄取被强烈抑制。这表明该酶通过阳离子非依赖性甘露糖6-磷酸受体掺入许旺细胞中。雪旺细胞中阳离子非依赖性甘露糖6-磷酸受体的低表达一定是其对本酶摄取低的原因之一。需要给予高剂量的酶或开发含有许多甘露糖6-磷酸残基的酶来改善法布里病神经病变。
Peripheral neuropathy is one of the important manifestations of Fabry disease. Enzyme replacement therapy with presently available recombinant alpha-galactosidases does not always improve the Fabry neuropathy. But the reason has not been determined yet. We established a Schwann cell line from Fabry mice, characterized it, and then examined the uptake of alpha-galactosidase by cells and its effect on the degradation of accumulated substrate. The cells exhibited a distinct Schwann cell morphology and biochemical phenotype (alpha-Galactosidase activity was deficient, and numerous cytoplasmic inclusion bodies were present in the cells). A recombinant alpha-galactosidase added to the culture medium was incorporated into the cultured Fabry Schwann cells dose dependently. But the increase in cell-associated enzyme activity was less than that in the cases of human and mouse Fabry fibroblasts. The administration of a high dose of the enzyme improved the pathological changes in cells, although a low dose of it did not. Cellular uptake of the enzyme was strongly inhibited in the presence of mannose 6-phosphate. This suggests that the enzyme is incorporated via cation-independent mannose 6-phosphate receptors in Schwann cells. The low expression of cation-independent mannose 6-phosphate receptors in Schwann cells must be one of the reasons their uptake of the present enzymes was low. The administration of a high dose of the enzyme or the development of an enzyme containing many mannose 6-phosphate residues is required to improve Fabry neuropathy.