Axonal regrowth after spinal cord injury via chondroitinase and the tissue plasminogen activator (tPA)/plasmin system.
Axonal regrowth after spinal cord injury via chondroitinase and the tissue plasminogen activator (tPA)/plasmin system.
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DOI：
10.1523/jneurosci.3339-11.2011
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发表时间：
2011-10-19
期刊：
影响因子：
--
通讯作者：
Tsirka SE
中科院分区：
文献类型：
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作者：
Bukhari N;Torres L;Robinson JK;Tsirka SE
脊髓损伤（SCI）由于轴突无法穿过已形成的瘢痕生长而导致永久性衰弱。硫酸软骨素蛋白聚糖（CSPG）的糖链和核心蛋白都抑制神经突再生。软骨素酶ABC（ChABC）降解糖链，并允许突触可塑性，这表明在糖链裂解后，发生额外的步骤，促进神经胶质瘢痕区域的容许微环境。我们报告说，清除的核心蛋白的tPA/纤溶酶蛋白水解系统部分有助于ChABC促进可塑性。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-/-）表现出衰减的神经突生长和迟钝的感觉和运动恢复，尽管ChABC治疗。共施用ChABC和纤溶酶增强了WT SCI小鼠中的tPA-/-表型并支持恢复。总的来说，这些研究结果表明，tPA/纤溶酶级联可能会采取行动的ChABC下游，使协同的感觉和运动的改善相比，每一个单独的治疗，并提出了一个潜在的新方法，以提高SCI后的功能恢复。
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 (CSPG) 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 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. Co-administration 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.