Myelin-associated glycoprotein and complementary axonal ligands, gangliosides, mediate axon stability in the CNS and PINS: Neuropathology and behavioral deficits in single- and double-null mice
Myelin-associated glycoprotein and complementary axonal ligands, gangliosides, mediate axon stability in the CNS and PINS: Neuropathology and behavioral deficits in single- and double-null mice
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DOI：
10.1016/j.expneurol.2005.04.017
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发表时间：
2005-09-01
影响因子：
5.3
通讯作者：
Schnaar, RL
中科院分区：
文献类型：
--
作者：
Pan, BH;Fromholt, SE;Schnaar, RL
髓磷脂和轴突上互补的相互作用分子需要长期的轴突-髓磷脂稳定性。它们的破坏导致轴突变性，促进脱髓鞘疾病的发病机制。髓磷脂相关糖蛋白（myelin -associated glycoprotein， MAG）是中枢和外周神经系统髓磷脂的一种次要成分，是唾液酸结合凝集素Siglec家族的一员，可与轴突表面的重要分子神经节苷脂GD1a和GT1b结合。缺乏神经节苷脂生物合成基因Galgt1的小鼠不能表达复杂的神经节苷脂，包括GD1a和GT1b。本研究在同一小鼠品系背景下，比较了Mag-null、Galgt1-null和double-null小鼠的CNS和PNS组织病理学和行为。当回交到99% C57BL/6菌株纯度时，与之前使用混合菌株背景的小鼠相比，Mag-null小鼠表现出明显的中枢神经系统，以及PNS，轴突变性。在相同的背景下，Mag-和galgt1缺失小鼠在数量和质量上表现出相似的CNS和PNS轴突退化，轴突直径和神经丝间距几乎相同的减少。双空小鼠也有类似的质量变化。与这些发现一致，Mag-和galgt1缺失的小鼠具有相似的运动行为缺陷，而双缺失的小鼠仅略微受损。尽管存在运动缺陷，Mag-和galgt1缺失的小鼠表现出过度活跃，自发运动活动明显高于野生型小鼠。这些数据表明，MAG和复杂的神经节苷脂有助于中枢神经系统和PNS的轴突稳定性。Galgt1-、Mag-和双空小鼠中类似的神经病理和行为缺陷支持Mag与神经节苷脂结合有助于轴突-髓磷脂长期稳定性的假设。(c) 2005爱思唯尔公司版权所有。
Complementary interacting molecules on myelin and axons are required for long-term axon-myelin stability. Their disruption results in axon degeneration, contributing to the pathogenesis of demyelinating diseases. Myelin-associated glycoprotein (MAG), a minor constituent of central and peripheral nervous system myelin, is a member of the Siglec family of sialic acid-binding lectins and binds to gangliosides GD1a and GT1b, prominent molecules on the axon surface. Mice lacking the ganglioside biosynthetic gene Galgt1 fail to express complex gangliosides, including GD1a and GT1b. In the current studies, CNS and PNS histopathology and behavior of Mag-null, Galgt1-null, and double-null mice were compared on the same mouse strain background. When back-crossed to > 99% C57BL/6 strain purity, Mag-null mice demonstrated marked CNS, as well as PNS, axon degeneration, in contrast to prior findings using mice of mixed strain background. On the same background, Mag- and Galgt1-null mice exhibited quantitatively and qualitatively similar CNS and PNS axon degeneration and nearly identical decreases in axon diameter and neurofilament spacing. Double-null mice had qualitatively similar changes. Consistent with these findings, Mag- and Galgt1-null mice had similar motor behavioral deficits, with double-null mice only modestly more impaired. Despite their motor deficits, Mag- and Galgt1-null mice demonstrated hyperactivity, with spontaneous locomotor activity significantly above that of wild type mice. These data demonstrate that MAG and complex gangliosides contribute to axon stability in both the CNS and PNS. Similar neuropathological and behavioral deficits in Galgt1-, Mag-, and double-null mice support the hypothesis that MAG binding to gangliosides contributes to long-term axon-myelin stability. (c) 2005 Elsevier Inc. All rights reserved.