Investigation of the role of MHC class I molecule on the demyelination in a model of genetic demyelination

本研究的目的是研究上调的MHC-I类分子在Twitcher脱髓鞘过程中的作用。Twitcher是一种遗传性脱髓鞘疾病--球状细胞白质营养不良的小鼠模型。Beta2-微球蛋白基因敲除与Twitcher小鼠的杂交使我们有可能启动这一计划。这两个突变的基因分型已经建立，但F2代存在生殖问题。因此，目前我们还没有完成观察。我们在Twitcher原型中检测了可能与MHC相关的细胞识别有关的病理机制，并得出了以下几个结论：1)随着脱髓鞘的进展，编码髓鞘碱性蛋白、髓鞘相关糖蛋白、髓鞘相关糖蛋白的基因的mRNA2)研究了引起抽动脑萎缩的少突胶质细胞的形态变化。随着疾病的发展，少突胶质细胞的细胞质和突起缩小，经原位末端标记法、DNA梯度法和电子显微镜观察，认为这是一种凋亡。3)在抽动脑中检测到了一种寡突胶质细胞相关蛋白--脂钙素型前列腺素D合成酶(Lipocalin型Prostaglandin D Synthase，LPG-PGDS)的表达。在脱髓鞘的过程中，这种酶呈进行性上调。它的分布、分布和形态发生了变化这与清道夫巨噬细胞的功能相反，可能表明L-PGDS可能具有保护少突胶质细胞免于退化的功能。Rodriguez等人已经对MHC I类分子在病毒诱导的脱髓鞘脱髓鞘中的病理作用进行了广泛的研究，他提出这种分子的存在对于脱髓鞘的进展和神经功能缺陷的发生是必不可少的。因此，重要的是检查即将到来的F2和F3后代，看看他的结论是否也适用于这种基因脱髓鞘。

The aim of this study was to investigate the role of upregulated MHC class I molecule in the demyelination of the twitcher, which is a murine model of genetic demyelinating disease, globoid cell leukodystrophy.The crossbreeding of beta2-microglobulin-knockout and twitcher mice makes us possible to start this project.The genotyping for both mutation has been established, however, there was a reproductive problem in F2 progeny.Thus, at present, we have not completed the observation.We examined the pathomechanism possibly linked to the MHC-related cell recognition in the twitcher prototype and made several conclusions :1) With progression of demyelination, mRNA for the genes encoding myelin basic protein, myelin-associated glycoprotein, proteolipid protein, and UDP-galactose : ceramide galactosyltransferase was downregulated in twitcher brains.2) Morphological alterations of oligodendrocytes leading to their depletion were studied in the twitcher.Oligodendroglial cytoplasm as well as processes became shrunken with the progression of the disease and these were thought to be apoptotic by TUNEL labeling, DNA laddering and electron microscopical observation.3) Expression of lipocalin-type prostaglandin D synthase (l-PGDS), an oligodendrocyte-associated protein, was examined in the twitcher brains.Unexpectedly, the enzyme is progressively upregulated during demyelination.Its distribution, which is inversely related to that of scavenger macrophages may suggest that l-PGDS may function to protect oligodendrocytes from degeneration.Rodriguez et al.have been performed extensive studies about the pathological role of MHC class I on the demyelination using virus-induced demyelination and he suggested that the existence of this molecule is essential for the progression of demyelination and the occurrence of neurological deficits.Thus it is important to examine the forthcoming F2 and F3 progeny to see if his conclusion is also the case in this genetic demyelination.