豚鼠朊病毒蛋白支持牛海绵状脑病和变异型克雅氏病朊病毒的快速传播。
Guinea Pig Prion Protein Supports Rapid Propagation of Bovine Spongiform Encephalopathy and Variant Creutzfeldt-Jakob Disease Prions.
作者信息
Watts Joel C, Giles Kurt, Saltzberg Daniel J, Dugger Brittany N, Patel Smita, Oehler Abby, Bhardwaj Sumita, Sali Andrej, Prusiner Stanley B
机构信息
Institute for Neurodegenerative Diseases, University of California, San Francisco, San Francisco, California, USA Department of Neurology, University of California, San Francisco, San Francisco, California, USA.
California Institute for Quantitative Biosciences (QB3), University of California, San Francisco, San Francisco, California, USA.
出版信息
J Virol. 2016 Oct 14;90(21):9558-9569. doi: 10.1128/JVI.01106-16. Print 2016 Nov 1.
UNLABELLED
The biochemical and neuropathological properties of bovine spongiform encephalopathy (BSE) and variant Creutzfeldt-Jakob disease (vCJD) prions are faithfully maintained upon transmission to guinea pigs. However, primary and secondary transmissions of BSE and vCJD in guinea pigs result in long incubation periods of ∼450 and ∼350 days, respectively. To determine if the incubation periods of BSE and vCJD prions could be shortened, we generated transgenic (Tg) mice expressing guinea pig prion protein (GPPrP). Inoculation of Tg(GPPrP) mice with BSE and vCJD prions resulted in mean incubation periods of 210 and 199 days, respectively, which shortened to 137 and 122 days upon serial transmission. In contrast, three different isolates of sporadic CJD prions failed to transmit disease to Tg(GPPrP) mice. Many of the strain-specified biochemical and neuropathological properties of BSE and vCJD prions, including the presence of type 2 protease-resistant PrP, were preserved upon propagation in Tg(GPPrP) mice. Structural modeling revealed that two residues near the N-terminal region of α-helix 1 in GPPrP might mediate its susceptibility to BSE and vCJD prions. Our results demonstrate that expression of GPPrP in Tg mice supports the rapid propagation of BSE and vCJD prions and suggest that Tg(GPPrP) mice may serve as a useful paradigm for bioassaying these prion isolates.
IMPORTANCE
Variant Creutzfeldt-Jakob disease (vCJD) and bovine spongiform encephalopathy (BSE) prions are two of the prion strains most relevant to human health. However, propagating these strains in mice expressing human or bovine prion protein has been difficult because of prolonged incubation periods or inefficient transmission. Here, we show that transgenic mice expressing guinea pig prion protein are fully susceptible to vCJD and BSE prions but not to sporadic CJD prions. Our results suggest that the guinea pig prion protein is a better, more rapid substrate than either bovine or human prion protein for propagating BSE and vCJD prions.
未标记
牛海绵状脑病（BSE）和变异型克雅氏病（vCJD）朊病毒的生化和神经病理学特性在传播给豚鼠后得到忠实地保留。然而，BSE和vCJD在豚鼠中的初次和二次传播分别导致约450天和约350天的长潜伏期。为了确定BSE和vCJD朊病毒的潜伏期是否可以缩短，我们培育了表达豚鼠朊病毒蛋白（GPPrP）的转基因（Tg）小鼠。用BSE和vCJD朊病毒接种Tg（GPPrP）小鼠分别导致平均潜伏期为210天和199天，在连续传代后缩短至137天和122天。相比之下，三种不同的散发性克雅氏病朊病毒分离株未能将疾病传播给Tg（GPPrP）小鼠。BSE和vCJD朊病毒的许多毒株特异性生化和神经病理学特性，包括2型蛋白酶抗性PrP的存在，在Tg（GPPrP）小鼠中传代时得以保留。结构建模显示，GPPrP中α螺旋1 N端区域附近的两个残基可能介导其对BSE和vCJD朊病毒的易感性。我们的结果表明，Tg小鼠中GPPrP的表达支持BSE和vCJD朊病毒的快速传播，并表明Tg（GPPrP）小鼠可能作为一种有用的范式用于这些朊病毒分离株的生物测定。
重要性
变异型克雅氏病（vCJD）和牛海绵状脑病（BSE）朊病毒是与人类健康最相关的两种朊病毒株。然而，由于潜伏期延长或传播效率低下，在表达人或牛朊病毒蛋白的小鼠中繁殖这些毒株一直很困难。在这里，我们表明表达豚鼠朊病毒蛋白的转基因小鼠对vCJD和BSE朊病毒完全易感，但对散发性克雅氏病朊病毒不易感。我们的结果表明，对于繁殖BSE和vCJD朊病毒，豚鼠朊病毒蛋白比牛或人朊病毒蛋白是更好、更快速的底物。
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