Transmission experiment of the model mouse expressed with the secretary from of the prion protein

本课题的目的是建立引入无义突变的转基因小鼠模型，使通常具有GPI （Glycosyl Phosphatidyl inositol）锚点的朊蛋白的GPI锚点信号失效，从而揭示分泌型朊蛋白。我们已经培育出以小鼠朊蛋白231号密码子为停止密码子的转基因小鼠，成功地培育出具有多淀粉样斑块的模型动物。对于该分泌型小鼠朊病毒蛋白，在重组分泌型低表达的情况下，从150天开始接种朊病毒后的潜伏期在90天内明显缩短，而在与野生型小鼠相同的中等表达水平下，潜伏期的缩短并不明显。此外，虽然引入了人小鼠嵌合体型基因，但同时显示GPI型和分泌型的模型动物潜伏期延长，甚至形成了与小鼠朊蛋白相似的淀粉样斑块。目前已制备出完整人型分泌型和GPI型的小鼠模型，其缩短潜伏期的效果尚在观察中。令人惊讶的是，小鼠分泌型朊病毒蛋白达到了蛋白酶抵抗的程度，这是朊病毒蛋白转化的标志。该模型有助于阐明朊病毒蛋白异常转化的机制。此外，朊病毒蛋白的分泌形式增强了模型动物滤泡树突状细胞检测朊病毒感染的敏感性。这些发现是随着目前正在申请中的新专利特征的出现而出现的。

The purpose of this project is to produce the transgenic mouse model that is introduced the nonsense mutation which makes the GPI anchor signal of the prion protein which usually possesses the GPI (Glycosyl Phosphatidyl inositol) anchor invalid reveals the prion protein of secretion type. We already produced the transgenic mouse which designates the codon 231 of the prion protein of the mouse as the stop codon, it has succeeded in the development of the model animal which has many amyloid plaques. As for this secretion type mouse prion protein, in case of the low expression level of the recombinant secretory form, the incubation period after the prion inoculation from 150 days is shortened dramatically on the 90 days, however, in case of the moderate expression level the same as the wild type mouse, it did not become clear for shortening in that incubation period. In addition, although the chimera type gene of the human mouse was introduced, the model animal which reveals the both of GPI type and secretion type had the elongated incubation period, even have the formaiton of amyloid plaques which were similar to the mouse prion protein. Presently, the mouse model which express the both of secretion type and GPI type of complete human type is produced, the shortening effect of the incubation period it is in the midst of observing. Surprisingly, the prion protein of secretion type of the mouse reached the point where the protease resistance which is a hallmark of the conversion of the prion protein is shown. This model is useful to the mechanism elucidation of abnormality conversion of the prion protein. In addition, the secretory form of prion protein enhanced the sensitivity to detect the prion infection in the follicular dendritic cells in the model animals. These findings is followed as the new patent characteristic which presently is in the midst of applying apperared.