The lysosomal sialic acid transporter sialin is required for normal CNS myelination.
The lysosomal sialic acid transporter sialin is required for normal CNS myelination.
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DOI：
10.1523/jneurosci.3005-09.2009
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发表时间：
2009-12-09
期刊：
影响因子：
--
通讯作者：
Reimer RJ
中科院分区：
文献类型：
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作者：
Prolo LM;Vogel H;Reimer RJ
Salla病和婴儿唾液酸储存病是常染色体隐性溶酶体储存疾病，由编码唾液素的基因突变引起，唾液素是一种膜蛋白，在唾液酸从降解的唾液糖缀合物中分离出来后，将游离唾液酸从溶酶体中转运出去。唾液酸在溶酶体中的积累定义了这些疾病，临床表型的特征是神经发育缺陷，包括严重的中枢神经系统（CNS）髓鞘化低下。在这项研究中，我们使用了一只唾液素缺乏的小鼠来研究唾液素的缺失是如何导致髓鞘形成缺陷的。sialin-/-小鼠的行为分析显示协调性差、癫痫发作和过早死亡。组织学、电镜和免疫印迹分析显示，中枢神经系统的髓鞘形成减少，但周围神经系统的神经元细胞结构和髓鞘形成正常。为了探讨中枢神经系统髓鞘形成的潜在机制，我们研究了视神经的髓鞘形成和少突胶质细胞的发育。我们发现sialin-/-小鼠视神经中有髓鞘的轴突数量减少，但有髓鞘的轴突上出现的髓鞘大致正常。少突胶质前体细胞迁移和密度正常；然而，在髓鞘形成的后期，有丝分裂后少突胶质细胞的数量明显减少，凋亡细胞的数量相应增加。这些发现表明，在少突胶质细胞谱系中，细胞成熟缺陷导致细胞凋亡增加，并成为髓鞘形成缺陷与唾液素丢失相关的基础。
Salla disease and infantile sialic acid storage disease are autosomal recessive lysosomal storage disorders caused by mutations in the gene encoding sialin, a membrane protein that transports free sialic acid out of the lysosome after it is cleaved from sialoglycoconjugates undergoing degradation. Accumulation of sialic acid in lysosomes defines these disorders and the clinical phenotype is characterized by neurodevelopmental defects, including severe central nervous system (CNS) hypomyelination. In this study we used a sialin deficient mouse to address how loss of sialin leads to the defect in myelination. Behavioral analysis of the sialin-/- mouse demonstrates poor coordination, seizures and premature death. Analysis by histology, electron microscopy and Western blotting, reveals a decrease in myelination of the CNS, but normal neuronal cytoarchitecture and normal myelination of the peripheral nervous system. To investigate potential mechanisms underlying CNS hypomyelination, we studied myelination and oligodendrocyte development in optic nerves. We found reduced numbers of myelinated axons in optic nerves from sialin-/- mice, but grossly normal appearing myelin on the axons that were myelinated. Migration and density of oligodendrocyte precursor cells were normal; however, there was a marked decrease in the number of postmitotic oligodendrocytes and an associated increase in the number of apoptotic cells during the later stages of myelinogenesis. These findings suggest that a defect in maturation of cells in the oligodendrocyte lineage leads to increased apoptosis and underlies the myelination defect associated with sialin loss.