Nodes of Ranvier and associated paranodal and juxtaparanodal domains along myelinated axons are essential for normal function of the peripheral and central nervous systems. Disruption of these domains as well as increases in the reactive carbonyl species methylglyoxal are implicated as a pathophysiology common to a wide variety of neurological diseases. Here, using an ex vivo nerve exposure model, we show that increasing methylglyoxal produces paranodal disruption, evidenced by disorganized immunostaining of axoglial cell-adhesion proteins, in both sciatic and optic nerves from wild-type mice. Consistent with previous studies showing that increase of methylglyoxal can alter intracellular calcium homeostasis, we found upregulated activity of the calcium-activated protease calpain in sciatic nerves after methylglyoxal exposure. Methylglyoxal exposure altered clusters of proteins that are known as calpain substrates: ezrin in Schwann cell microvilli at the perinodal area and zonula occludens 1 in Schwann cell autotypic junctions at paranodes. Finally, treatment with the calpain inhibitor calpeptin ameliorated methylglyoxal-evoked ezrin loss and paranodal disruption in both sciatic and optic nerves. Our findings strongly suggest that elevated methylglyoxal levels and subsequent calpain activation contribute to the disruption of specialized axoglial domains along myelinated nerve fibers in neurological diseases.

中文翻译：

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甲基乙二醛通过钙蛋白酶激活破坏淋巴结旁神经交界处。

沿髓鞘轴突的Ranvier结节以及相关的旁结节和近旁结节域对于周围和中枢神经系统的正常功能至关重要。这些结构域的破坏以及反应性羰基物质甲基乙二醛的增加被认为是多种神经系统疾病共有的病理生理学。在这里，使用离体神经暴露模型，我们显示出增加的甲基乙二醛会产生偏执狂破坏，这是由野生型小鼠的坐骨神经和视神经中轴突胶质细胞粘附蛋白的无序免疫染色所证明的。与以前的研究表明甲基乙二醛的增加可以改变细胞内钙稳态有关，我们发现甲基乙二醛暴露后坐骨神经中钙激活的蛋白酶钙蛋白酶的活性上调。甲基乙二醛暴露会改变称为钙蛋白酶底物的蛋白质簇：在结节区的施旺细胞微绒毛中的ezrin和在节旁的施旺细胞自型结中的小带闭塞1。最后，用钙蛋白酶抑制剂钙肽蛋白治疗可改善坐骨神经和视神经的甲基乙二醛诱发的ezrin丢失和偏瘫破坏。我们的发现强烈表明，甲基乙二醛水平升高和随后的钙蛋白酶激活会导致神经疾病中沿髓鞘神经纤维的特定轴突结构域的破坏。钙蛋白酶抑制剂钙蛋白酶的治疗改善了坐骨神经和视神经的甲基乙二醛诱发的ezrin丢失和偏瘫破坏。我们的发现强烈表明，甲基乙二醛水平升高和随后的钙蛋白酶激活会导致神经疾病中沿髓鞘神经纤维的特定轴突结构域的破坏。钙蛋白酶抑制剂钙蛋白酶的治疗改善了坐骨神经和视神经的甲基乙二醛诱发的ezrin丢失和偏瘫破坏。我们的发现强烈表明，甲基乙二醛水平升高和随后的钙蛋白酶激活会导致神经疾病中沿髓鞘神经纤维的特定轴突结构域的破坏。