Reduced raft-association of NF155 in active MS-lesions is accompanied by the disruption of the paranodal junction
Reduced raft-association of NF155 in active MS-lesions is accompanied by the disruption of the paranodal junction
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DOI：
10.1002/glia.20510
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发表时间：
2007-06-01
期刊：
影响因子：
6.2
通讯作者：
Hoekstra, Dick
中科院分区：
文献类型：
--
作者：
Maier, Olaf;Baron, Wia;Hoekstra, Dick
neurofascin 155（NF 155）是建立结旁轴-胶质连接所必需的，这是髓鞘和轴突之间的主要相互作用位点。已经表明，NF 155的分布在脱髓鞘疾病如多发性硬化症（MS）中改变。然而，人们对这些变化背后的生化机制知之甚少。因此，我们比较了NF 155在死后组织的活动性和慢性非活动性MS病变与白色物质从健康对照。尽管NF 155在所有对照白色物质样品中显示出非常相似的表达，但在MS病变中观察到强烈的个体差异，在大多数样品中NF 155水平降低。同时，在MS病变中NF 155片段增加，表明NF 155在病变部位发生蛋白质降解。有趣的是，无论NF 155的量如何，NF 155与膜微区（筏）的结合在所有病变中均减少，表明NF 155的膜结合通常受到影响。因此，进行髓鞘分级实验来分析脱髓鞘过程中结旁蛋白的命运。虽然NF 155富含来自对照白色物质和活动性MS病变的重髓鞘，但Caspr 1/paranodin与重髓鞘的关联在MS病变中被消除，表明结旁连接被破坏。总之，数据支持NF 155的有效筏缔合对于结旁连接的组装至关重要的假设，并证明NF 155与脂筏的缔合减少伴随结旁连接的分解，从而有助于MS的脱髓鞘过程。（c）2007 Wiley-Liss，Inc.
Neurofascin155 (NF155) is required for the establishment of the paranodal axo-glial junction, the predominant interaction site between myelin and axon. It has been shown that the distribution of NF155 is altered in demyelinating diseases such as multiple sclerosis (MS). However, little is known about the biochemical mechanisms underlying these changes. We therefore compared NF155 in postmortem tissue of active and chronic inactive MS lesions with white matter from healthy controls. Although NF155 showed a very similar expression in all control white matter samples, a strong individual variation was observed in MS-lesions with NF155-levels reduced in most samples. At the same time an NF155-fragment was increased in MS-lesions, suggesting that NF155 is subject to protein degradation in lesion sites. Interestingly, the association of NF155 to membrane microdomains (rafts) was reduced in all lesions, irrespective of the amount of NF155, indicating that membrane association of NF155 was generally affected. Therefore, myelin fractionation experiments were performed to analyze the fate of paranodal proteins during demyelination. Although NF155 was enriched in heavy myelin from both control white matter and active MS-lesions, association of Caspr1/paranodin with heavy myelin was abolished in MS-lesions, demonstrating that paranodal junctions are disrupted. In conclusion, the data support the hypothesis that efficient raft-association of NF155 is essential for the assembly of the paranodal junction and demonstrate that reduced association of NF155 to lipid rafts is accompanied by the disassembly of the paranodal junction and thus contributes to the demyelination process in MS. (c) 2007 Wiley-Liss, Inc.