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ticker脱髓鞘中的作用，这是一种遗传性脱髓鞘疾病，球状细胞脑白质营养不良的小鼠模型。β 2-微球蛋白敲除小鼠和ticker小鼠的杂交使我们有可能开始这个项目。两种突变的基因型已经建立，但是在F2后代中存在生殖问题。因此，目前，我们还没有完成观察。我们检查了可能与抽搐原型中MHC相关细胞识别相关的病理机制，并得出几个结论：1）随着脱髓鞘的进展，编码髓鞘碱性蛋白、髓鞘相关糖蛋白、蛋白脂质蛋白和UDP-半乳糖的基因的mRNA：神经酰胺半乳糖基转移酶在抽搐的大脑中下调。在twitcher中研究了导致其耗尽的少突胶质细胞的形态学改变。TUNEL标记、DNA梯状电泳和电子显微镜观察显示，这些疾病被认为是细胞凋亡。3）检测了少突胶质细胞相关蛋白脂质运载蛋白型前列腺素D合成酶（l-PGDS）在抽搐者脑中的表达。出乎意料的是，该酶在脱髓鞘过程中进行性上调。其分布，这与清道夫巨噬细胞的负相关，可能表明L-PGDS可能具有保护少突胶质细胞免于变性的功能，Rodriguez等已经对MHC I类在少突胶质细胞中的病理作用进行了广泛的研究。因此，重要的是要检查即将到来的F2和F3后代，看看他的结论是否也适用于这种遗传性脱髓鞘。

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.