Glial Sulfatides and Neuronal Complex Gangliosides Are Functionally Interdependent in Maintaining Myelinating Axon Integrity
Glial Sulfatides and Neuronal Complex Gangliosides Are Functionally Interdependent in Maintaining Myelinating Axon Integrity
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DOI：
10.1523/jneurosci.2095-18.2018
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发表时间：
2019-01-02
影响因子：
5.3
通讯作者：
Willison, Hugh J.
中科院分区：
文献类型：
--
作者：
McGonigal, Rhona;Barrie, Jennifer A.;Willison, Hugh J.
脑硫脂和神经节苷脂是筏相关糖脂，对于维持有髓神经的完整性至关重要。硫脑苷脂（脑苷脂磺基转移酶敲除，CST-/-）或复合神经节苷脂（β-1,4-N-乙酰半乳糖胺基转移酶敲除，GalNAc-T-/-）缺陷的小鼠在生命早期和年龄依赖性神经变性中表现出朗飞节（NoR）蛋白质的显着紊乱。神经元而不是神经胶质复合神经节苷脂的丧失支撑了 GalNAc-T-/- 表型，如神经元或神经胶质特异性拯救所示，而硫脑苷脂主要在神经胶质膜中表达和发挥作用。 CST-/-、GalNAc-T-/- 和轴胶质蛋白缺陷小鼠的 NoR 表型相似，表明这些糖脂可以稳定轴胶质连接处的膜蛋白，包括神经成束蛋白 155 (NF155) 和髓磷脂相关糖蛋白 (MAG)。为了评估脑硫脂和神经节苷脂之间的功能相互作用，将 CST-/- 和 GalNAc-T-/- 基因型进行了杂交。 CST-/- X Ga/NAc-T-/- 小鼠正常发育至出生后第 10 天 (P10)，但全部在 P20 和 P25 之间死亡，与髓鞘形成高峰期一致。任一性别的超微结构、免疫组织学和生化分析均显示 NoR 处广泛的轴突变性和轴突胶质细胞连接处的破坏。除了硫苷脂依赖性 NF155 缺失外，与 WT 和单脂缺陷小鼠相比，CST-/- X GalNAc-T-/- 小鼠中枢神经系统髓磷脂中的 MAG 蛋白水平显着降低。 CST-/- X GalNAc-T-/- 表型通过复杂神经节苷脂的神经元特异性表达完全恢复到 CST-/- 小鼠的表型，但不是通过其神经胶质特异性表达或 a 系列神经节苷脂的整体表达。这些数据表明，神经胶质细胞膜和神经元膜上的硫苷脂和复合b系列神经节苷脂分别协同作用，促进NF155和MAG维持正常神经功能所必需的稳定的轴-神经胶质相互作用。
Sulfatides and gangliosides are raft-associated glycolipids essential for maintaining myelinated nerve integrity. Mice deficient in sulfatide (cerebroside sulfotransferase knock-out, CST-/-) or complex gangliosides (beta-1,4-N-acetylegalactosaminyltransferasel knock- out, GalNAc-T-/-) display prominent disorganization of proteins at the node of Ranvier (NoR) in early life and age-dependent neurodegeneration. Loss of neuronal rather than glial complex gangliosides underpins the GalNAc-T-/- phenotype, as shown by neuron- or glial-specific rescue, whereas sulfatide is principally expressed and functional in glial membranes. The similarities in NoR phenotype of CST-/-, GalNAc-T-/-, and axo- glial protein-deficient mice suggests that these glycolipids stabilize membrane proteins including neurofascin155 (NF155) and myelin-associated glycoprotein (MAG) at axo- glial junctions. To assess the functional interactions between sulfatide and gangliosides, CST-/- and GalNAc-T-/- genotypes were interbred. CST-/- X Ga/NAc-T-/- mice develop normally to postnatal day 10 (P10), but all die between P20 and P25, coinciding with peak myelination. Ultrastructural, immunohistological, and biochemical analysis of either sex revealed widespread axonal degeneration and disruption to the axo- glial junction at the NoR. In addition to sulfatide-dependent loss of NF155, CST-/- X GalNAc-T-/- mice exhibited a major reduction in MAG protein levels in CNS myelin compared with WT and single-lipid-deficient mice. The CST-/- X GalNAc-T-/- phenotype was fully restored to that of CST-/- mice by neuron-specific expression of complex gangliosides, but not by their glial-specific expression nor by the global expression of a-series gangliosides. These data indicate that sulfatide and complex b-series gangliosides on the glial and neuronal membranes, respectively, act in concert to promote NF155 and MAG in maintaining the stable axo-glial interactions essential for normal nerve function.