A sulfated carbohydrate epitope inhibits axon regeneration after injury
A sulfated carbohydrate epitope inhibits axon regeneration after injury
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DOI：
10.1073/pnas.1121318109
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发表时间：
2012-03-27
影响因子：
11.1
通讯作者：
Hsieh-Wilson, Linda C.
中科院分区：
文献类型：
--
作者：
Brown, Joshua M.;Xia, Jiang;Hsieh-Wilson, Linda C.
硫酸软骨素蛋白聚糖（CSPGs）是中枢神经系统（CNS）轴突再生的主要障碍，但其多糖结构的多样性阻碍了对其生理活性的构效关系的研究。通过利用我们化学合成特定寡糖的能力，我们证明了CSPGs上的糖表位硫酸软骨素-E（CS-E）有效抑制轴突生长。去除CS-E基序显著减弱CSPGs对轴突生长的抑制活性。此外，CS-E作为蛋白质识别元件发挥作用以接合包括跨膜蛋白酪氨酸磷酸酶PTP σ的受体，从而触发抑制轴突生长的下游途径。最后，使用CS-E特异性抗体掩蔽CS-E基序逆转了CSPGs的抑制活性并刺激了体内轴突再生。这些结果表明，硫酸软骨素多糖内的特定糖表位可以指导重要的生理过程，并提供新的治疗策略，以再生中枢神经系统损伤后的轴突。
Chondroitin sulfate proteoglycans (CSPGs) represent a major barrier to regenerating axons in the central nervous system (CNS), but the structural diversity of their polysaccharides has hampered efforts to dissect the structure-activity relationships underlying their physiological activity. By taking advantage of our ability to chemically synthesize specific oligosaccharides, we demonstrate that a sugar epitope on CSPGs, chondroitin sulfate-E (CS-E), potently inhibits axon growth. Removal of the CS-E motif significantly attenuates the inhibitory activity of CSPGs on axon growth. Furthermore, CS-E functions as a protein recognition element to engage receptors including the transmembrane protein tyrosine phosphatase PTP sigma, thereby triggering downstream pathways that inhibit axon growth. Finally, masking the CS-E motif using a CS-E-specific antibody reversed the inhibitory activity of CSPGs and stimulated axon regeneration in vivo. These results demonstrate that a specific sugar epitope within chondroitin sulfate polysaccharides can direct important physiological processes and provide new therapeutic strategies to regenerate axons after CNS injury.