Functions of chondroitin sulfate polysaocharide in the central nervous system

研究了硫酸软骨素蛋白多糖（CSPGs）在中枢神经系统中的功能；我们最初在发育中的大鼠脑中发现了脑特异性CSPG神经聚糖C （NGC）和作为脑细胞主要微环境分子的硫酸软骨素（CS）多糖的功能分析。神经聚糖c位点定向诱变的功能表明，在小鼠NGC核心蛋白的S^<123>处引入了一条CS链。除了这个cs -附着结构域，NGC的胞外区域还包含另外两个独特的结构域；一个酸性氨基酸簇（aa结构域）和一个表皮生长因子样结构域（egf结构域）。CS-和aa -结构域对生长因子midkine具有较高的亲和力。AA-和EGF-结构域对神经突延伸均有促进作用。egf结构域促进具有egf受体的细胞生长。获得低表达和不表达NGC的小鼠品系。这些老鼠表现出行为异常。这些结果表明NGC在中枢神经系统中是一种功能分子。从发育中的大鼠脑中分离纯化的硫酸软骨素多糖促进成纤维细胞生长因子(FGF)-2介导的神经干细胞增殖。CS、CS- b和CS- e的商业制剂也能促进fgf -2介导的神经干细胞生长，这表明CS多糖中含有伊杜醛酸的结构（b结构）和galnac -4,6-二硫酸盐形成的过硫酸盐结构（e结构）参与了这种促进神经干细胞生长的作用。此外，CS-E保护神经元免受谷氨酸诱导的兴奋性神经细胞死亡，这种死亡发生在脑损伤后立即发生。因此，CS多糖在大脑中是一种生物活性分子。

Functions of chondroitin sulfate proteoglycans (CSPGs) in the central nervous system were investigated in the two ways; functional analyses of a brain-specific CSPG, neuroglycan C (NGC), that we originally found in the developing rat brain and chondroitin sulfate (CS) polysaccharides as a major microenvironmental molecule of cells in the brain.I. Functions of neuroglycan CSite-directed mutagenesis revealed that a CS chain was introduced to S^<123> of the mouse NGC core protein. In addition to this CS-attachment domain, the extracellular region of NGC contains two other unique domains; a cluster of acidic amino acids (AA-domain) and an epidermal growth factor-like domain (EGF-domain). Both CS- and AA-domains had a high affinity to midkine, a growth factor. Both AA- and EGF- domains have a promotive activity for neurite extension. EGF-domain promotes growth of cells with EGF-receptors. Mouse strains with low and no expressions of NGC were produced. These mice show behavioral abnormalities. All these findings indicate that NGC is a functional molecule in the central nervous system.II. Functions of chondroitin sulfate polysaccharidesCS polysaccharides isolated and purified from developing rat brains promote fibroblast growth factor (FGF)-2-mediated proliferation of neural stem cells. Commercial preparations of CS, CS-B and CS-E, also promote FGF-2-mediated neural stem cell growth, suggesting that an iduronic acid-containing structure (B-structure) and an over sulfated structure formed by GalNAc-4,6-disulfate (E-structure) in the CS polysaccharides are involved in this promotion of neural stem cell growth. Additionally, CS-E protects neurons from glutamate-induced excitatory neural cell death, that occurs immediately after brain injuries. Thus, CS polysaccharide is a bioactive molecule in the brain.