Dissociation of pathological and molecular phenotype of variant Creutzfeldt-Jakob disease in transgenic human prion protein 129 heterozygous mice
Dissociation of pathological and molecular phenotype of variant Creutzfeldt-Jakob disease in transgenic human prion protein 129 heterozygous mice
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DOI：
10.1073/pnas.0604292103
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发表时间：
2006-07-11
影响因子：
11.1
通讯作者：
Collinge, John
中科院分区：
文献类型：
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作者：
Asante, Emmanuel A.;Linehan, Jacqueline M.;Collinge, John
所有经神经病理学证实的变异型克雅氏病（vCJD），其特征是大脑中有丰富的丰富斑块和4型疾病相关朊蛋白（PrPSc），在PRNP多态性残基129处均为蛋氨酸纯合。vCJD的独特的神经病理和分子表型可以在Prnp-null转基因小鼠中忠实地再现，这些小鼠纯合人PrP M129，而不是V129，其中传播了一种独特的朊病毒株。我们在转基因小鼠中模拟了最常见的PRNP基因型129MV杂合子的易感性，结果显示，4型PrPSc的繁殖与典型的vCJD神经病理无关。这些小鼠在受到牛海绵状脑病（BSE）朊病毒或人传代疯牛病（vCJD）朊病毒的攻击后，根据接种物的来源，可以产生四种不同的疾病表型。vcjd攻毒小鼠的朊病毒感染率高于bse攻毒小鼠。这些数据表明，人类PRNP 129杂合子比牛疯牛病朊病毒更容易感染vCJD朊病毒，并且可能表现出与vCJD不同的神经病理表型。
All neuropathologically confirmed cases of variant Creutzfeldt-Jakob disease (vCJD), characterized by abundant florid plaques and type 4 disease-related prion protein (PrPSc) in the brain, have been homozygous for methionine at polymorphic residue 129 of PRNP. The distinctive neuropathological and molecular phenotype of vCJD can be faithfully recapitulated in Prnp-null transgenic mice homozygous for human PrP M129 but not V129, where a distinct prion strain is propagated. Here we model susceptibility of 129MV heterozygotes, the most common PRNP genotype, in transgenic mice and show that, remarkably, propagation of type 4 PrPSc was not associated with characteristic vCJD neuropathology. Depending on the source of the inoculum these mice can develop four distinct disease phenotypes after challenge with bovine spongiform encephalopathy (BSE) prions or vCJD (human-passaged BSE) prions. vCJD-challenged mice had higher attack rates of prion infection than BSE-challenged recipients. These data argue that human PRNP 129 heterozygotes will be more susceptible to infection with vCJD prions than to cattle BSE prions and may present with a neuropathological phenotype distinct from vCJD.