Department of Pharmacological Sciences, Stony Brook University, New York, NY 11794-8651, USA.
J Neurosci. 2011 Oct 19;31(42):14931-43. doi: 10.1523/JNEUROSCI.3339-11.2011.
Spinal cord injury (SCI) causes permanent debilitation due to the inability of axons to grow through established scars. Both the sugar chains and core proteins of chondroitin sulfate proteoglycans (CSPGs) are inhibitory for neurite regrowth. Chondroitinase ABC (ChABC) degrades the sugar chains and allows for synaptic plasticity, suggesting that after the sugar chain cleavage additional steps occur promoting a permissive microenvironment in the glial scar region. We report that the clearance of the core protein by the tissue plasminogen activator (tPA)/plasmin proteolytic system partially contributes to ChABC-promoted plasticity. tPA and plasmin are upregulated after SCI and degrade the deglycosylated CSPG proteins. Mice lacking tPA (tPA(-/-)) exhibit attenuated neurite outgrowth and blunted sensory and motor recovery despite ChABC treatment. Coadministration of ChABC and plasmin enhanced the tPA(-/-) phenotype and supported recovery in WT SCI mice. Collectively, these findings show that the tPA/plasmin cascade may act downstream of ChABC to allow for synergistic sensory and motor improvement compared with each treatment alone and suggest a potential new approach to enhance functional recovery after SCI.
脊髓损伤 (SCI) 会导致轴突无法穿过已形成的疤痕而导致永久性的衰弱。硫酸软骨素蛋白聚糖 (CSPG) 的糖链和核心蛋白都对轴突再生有抑制作用。软骨素酶 ABC (ChABC) 可降解糖链，促进突触可塑性，这表明在糖链切割后，还会发生其他步骤，促进神经胶质瘢痕区域的许可微环境。我们报告称，组织纤溶酶原激活物 (tPA)/纤溶酶蛋白水解系统通过清除核心蛋白在 ChABC 促进的可塑性中起部分作用。tPA 和纤溶酶在 SCI 后上调，并降解去糖基化的 CSPG 蛋白。缺乏 tPA 的小鼠 (tPA(-/-)) 尽管接受了 ChABC 治疗，但神经突生长减弱，感觉和运动恢复迟钝。ChABC 和纤溶酶联合给药增强了 tPA(-/-)表型，并支持 WT SCI 小鼠的恢复。综上所述，这些发现表明 tPA/纤溶酶级联反应可能是 ChABC 的下游作用机制，与单独每种治疗相比，可协同改善感觉和运动功能，并为 SCI 后增强功能恢复提供一种新的潜在方法。
