Department of Anatomy and Neurobiology, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA.
Brain. 2010 Feb;133(Pt 2):389-405. doi: 10.1093/brain/awp341. Epub 2010 Feb 3.
Stability of the myelin-axon unit is achieved, at least in part, by specialized paranodal junctions comprised of the neuronal heterocomplex of contactin and contactin-associated protein and the myelin protein neurofascin 155. In multiple sclerosis, normal distribution of these proteins is altered, resulting in the loss of the insulating myelin and consequently causing axonal dysfunction. Previously, this laboratory reported that mice lacking the myelin-enriched lipid sulphatide are characterized by a progressive deterioration of the paranodal structure. Here, it is shown that this deterioration is preceded by significant loss of neurofascin 155 clustering at the myelin paranode. Interestingly, prolonged electrophoretic separation revealed the existence of two neurofascin 155 bands, neurofascin 155 high and neurofascin 155 low, which are readily observed following N-linked deglycosylation. Neurofascin 155 high is observed at 7 days of age and reaches peak expression at one month of age, while neurofascin 155 low is first observed at 14 days of age and constantly increases until 5 months of age. Studies using conditional neurofascin knockout mice indicated that neurofascin 155 high and neurofascin 155 low are products of the neurofascin gene and are exclusively expressed by oligodendrocytes within the central nervous system. Neurofascin 155 high is a myelin paranodal protein while the distribution of neurofascin 155 low remains to be determined. While neurofascin 155 high levels are significantly reduced in the sulphatide null mice at 15 days, 30 days and 4 months of age, neurofascin 155 low levels remain unaltered. Although maintained at normal levels, neurofascin 155 low is incapable of preserving paranodal structure, thus indicating that neurofascin 155 high is required for paranodal stability. Additionally, comparisons between neurofascin 155 high and neurofascin 155 low in human samples revealed a significant alteration, specifically in multiple sclerosis plaques.
髓鞘-轴突单元的稳定性至少部分是通过特殊的连接蛋白和接触蛋白相关蛋白和神经束蛋白 155 组成的神经节段连接来实现的。在多发性硬化症中，这些蛋白质的正常分布发生改变，导致绝缘髓鞘丢失，进而导致轴突功能障碍。此前，本实验室报道称，富含髓鞘的脂质硫脂缺乏的小鼠表现出连接蛋白节段结构的进行性恶化。在这里，研究表明，这种恶化之前，神经束蛋白 155 在髓鞘连接蛋白处的聚类显著丢失。有趣的是，延长电泳分离显示存在两种神经束蛋白 155 带，神经束蛋白 155 高和神经束蛋白 155 低，这两种带在 N 连接糖基化后很容易观察到。神经束蛋白 155 高在 7 天时出现，并在 1 月龄时达到峰值表达，而神经束蛋白 155 低在 14 天时首次出现，并持续增加到 5 月龄。使用条件性神经束蛋白敲除小鼠的研究表明，神经束蛋白 155 高和神经束蛋白 155 低是神经束蛋白基因的产物，仅由中枢神经系统中的少突胶质细胞表达。神经束蛋白 155 高是髓鞘连接蛋白，而神经束蛋白 155 低的分布尚待确定。尽管在 15 天、30 天和 4 月龄的硫脂缺失小鼠中神经束蛋白 155 高的水平显著降低，但神经束蛋白 155 低的水平仍未改变。尽管保持在正常水平，但神经束蛋白 155 低不能维持连接蛋白节段的结构，因此表明神经束蛋白 155 高是连接蛋白节段稳定性所必需的。此外，在人类样本中比较神经束蛋白 155 高和神经束蛋白 155 低发现存在显著改变，特别是在多发性硬化斑块中。
