A domain responsible for spontaneous conversion of bank vole prion protein
A domain responsible for spontaneous conversion of bank vole prion protein
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DOI：
10.1111/bpa.12638
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发表时间：
2019-03-01
期刊：
影响因子：
6.4
通讯作者：
Kitamoto, Tetsuyuki
中科院分区：
文献类型：
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作者：
Kobayashi, Atsushi;Matsuura, Yuichi;Kitamoto, Tetsuyuki
田鼠是一种小型啮齿动物，对不同的朊病毒株感染表现出高度易感性。为了确定是否银行田鼠朊病毒疾病的易感性增加可以归因于银行田鼠朊病毒蛋白（PrP）的内在性质或宿主因素以外的其他PrP，我们产生了转基因小鼠过表达银行田鼠PrP。这些转基因小鼠自发地发展为神经系统疾病，具有海绵状变化和异常PrP在大脑中的积累。然后，我们生产了过表达嵌合小鼠/银行田鼠PrP的转基因小鼠，其不同于小鼠PrP仅在位于C-末端的两个残基，以确定诱导自发产生异常PrP的最小必需结构域。这些转基因小鼠还出现了自发性神经系统疾病，伴有海绵状变化和异常PrP在大脑中的积累。此外，敲入小鼠表达银行田鼠PrP在相同的水平，野生型小鼠没有自发性疾病，但表现出高的易感性感染不同的朊病毒株，类似于银行田鼠。两者合计，这些研究结果表明，银行田鼠PrP具有很高的倾向，在自发性疾病和朊病毒感染的构象转换，可能是由于特征的C-末端结构域的结构特性。
Bank vole is a small rodent that shows high susceptibility to infection with diverse prion strains. To determine whether the increased susceptibility of bank voles to prion diseases can be attributed to the intrinsic nature of bank vole prion protein (PrP) or to host factors other than PrP, we produced transgenic mice overexpressing bank vole PrP. These transgenic mice spontaneously developed neurological illness with spongiform changes and the accumulation of abnormal PrP in the brain. Then, we produced transgenic mice overexpressing chimeric mouse/bank vole PrP, which differs from mouse PrP only at two residues located at the C-terminus, to determine the minimum essential domain for the induction of spontaneous generation of abnormal PrP. These transgenic mice also developed spontaneous neurological illness with spongiform changes and the accumulation of abnormal PrP in the brain. In addition, knock-in mice expressing bank vole PrP at the same level as that of wild-type mice did not develop spontaneous disease but showed high susceptibility to infection with diverse prion strains, similarly to bank voles. Taken together, these findings show that bank vole PrP has a high propensity for the conformational conversion both in spontaneous disease and in prion infection, probably due to the characteristic structural properties of the C-terminal domain.