A naturally occurring variant of the human prion protein completely prevents prion disease.
A naturally occurring variant of the human prion protein completely prevents prion disease.
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DOI：
10.1038/nature14510
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发表时间：
2015-06-25
期刊：
影响因子：
64.8
通讯作者：
Collinge, John
中科院分区：
文献类型：
--
作者：
Asante, Emmanuel A.;Smidak, Michelle;Grimshaw, Andrew;Houghton, Richard;Tomlinson, Andrew;Jeelani, Asif;Jakubcova, Tatiana;Hamdan, Shyma;Richard-Londt, Angela;Linehan, Jacqueline M.;Brandner, Sebastian;Alpers, Michael;Whitfield, Jerome;Mead, Simon;Wadsworth, Jonathan D. F.;Collinge, John
哺乳动物朊病毒是由错误折叠的细胞朊蛋白（PrP）组装而成的一种可引起致命性神经退行性疾病的传染性因子。一种新的PrP变异体G127 V在库鲁病流行期间处于积极的进化选择之下，库鲁病是巴布亚新几内亚Fore人群的一种获得性朊病毒病流行病，并且似乎在杂合状态下提供了强大的抗疾病保护。我们现在已经研究了这种变体的保护作用及其与全球常见的M129 V PrP多态性的相互作用; V127仅见于M129 PRNP等位基因。在这里，我们证明，转基因小鼠表达的变体和野生型人类PrP是完全抵抗库鲁和经典的CJD朊病毒（这是非常相似的），但可以感染变异CJD朊病毒，人类朊病毒株导致暴露于BSE朊病毒，而福尔没有暴露。然而，值得注意的是，仅表达PrP V127的小鼠对所有朊病毒株都具有完全抗性，这表明与M129 V不同的分子机制，M129 V在杂合状态下提供了对经典CJD和库鲁病的相对保护。事实上，在脊椎动物进化过程中，在一个不变的残基上进行的单个氨基酸替换（G→V）与蛋白质的缺失一样具有保护作用。在表达不同比例的变体和野生型PrP的转基因小鼠中的进一步研究表明，PrPV 127不仅对朊病毒转化完全无效，而且作为野生型朊病毒繁殖的有效剂量依赖性抑制剂。
Mammalian prions, transmissible agents causing lethal neurodegenerative diseases, are composed of assemblies of misfolded cellular prion protein (PrP) . A novel PrP variant, G127V, was under positive evolutionary selection during the epidemic of kuru, an acquired prion disease epidemic of the Fore population in Papua New Guinea, and appeared to provide strong protection against disease in the heterozygous state. We have now investigated the protective role of this variant and its interaction with the common worldwide M129V PrP polymorphism; V127 was seen exclusively on a M129 PRNP allele. Here we demonstrate that transgenic mice expressing both variant and wild type human PrP are completely resistant to both kuru and classical CJD prions (which are closely similar) but can be infected with variant CJD prions, a human prion strain resulting from exposure to BSE prions to which the Fore were not exposed. Remarkably however, mice expressing only PrP V127 were completely resistant to all prion strains demonstrating a different molecular mechanism to M129V, which provides its relative protection against classical CJD and kuru in the heterozygous state. Indeed this single amino acid substitution (G→V) at a residue invariant in vertebrate evolution is as protective as deletion of the protein. Further study in transgenic mice expressing different ratios of variant and wild type PrP indicates that not only is PrP V127 completely refractory to prion conversion, but acts as a potent dose-dependent inhibitor of wild type prion propagation.
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影响因子：
56.9
作者：
Wadsworth, JDF;Asante, EA;Collinge, J
通讯作者：
Collinge, J
DOI：
10.1073/pnas.0604292103
发表时间：
2006-07-11
影响因子：
11.1
作者：
Asante, Emmanuel A.;Linehan, Jacqueline M.;Collinge, John
通讯作者：
Collinge, John
DOI：
10.1073/pnas.0809170106
发表时间：
2009-02-24
影响因子：
11.1
作者：
Antonyuk, S. V.;Trevitt, C. R.;Collinge, J.
通讯作者：
Collinge, J.
影响因子：
64.8
作者：
PALMER, MS;DRYDEN, AJ;COLLINGE, J
通讯作者：
COLLINGE, J
影响因子：
2.5
作者：
Asante, EA;Li, YG;Collinge, J
通讯作者：
Collinge, J