Isolation of novel synthetic prion strains by amplification in transgenic mice coexpressing wild-type and anchorless prion proteins.
Isolation of novel synthetic prion strains by amplification in transgenic mice coexpressing wild-type and anchorless prion proteins.
复制标题
通过在共表达野生型和无锚定朊病毒蛋白的转基因小鼠中扩增来分离新型合成朊病毒株。
DOI：
10.1128/jvi.01353-12
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发表时间：
2012
影响因子：
5.4
通讯作者：
Baron,GeraldS
中科院分区：
文献类型：
--
作者：
Raymond,GregoryJ;Race,Brent;Hollister,JasonR;Offerdahl,DanielleK;Moore,RogerA;Kodali,Ravindra;Raymond,LynneD;Hughson,AndrewG;Rosenke,Rebecca;Long,Dan;Dorward,DavidW;Baron,GeraldS
Mammalian prions are thought to consist of misfolded aggregates (protease-resistant isoform of the prion protein [PrPres]) of the cellular prion protein (PrPC). Transmissible spongiform encephalopathy (TSE) can be induced in animals inoculated with recombinant PrP (rPrP) amyloid fibrils lacking mammalian posttranslational modifications, but this induction is inefficient in hamsters or transgenic mice overexpressing glycosylphosphatidylinositol (GPI)-anchored PrPC. Here we show that TSE can be initiated by inoculation of misfolded rPrP into mice that express wild-type (wt) levels of PrPCand that synthetic prion strain propagation and selection can be affected by GPI anchoring of the host's PrPC. To create prionsde novo, we fibrillized mouse rPrP in the absence of molecular cofactors, generating fibrils with a PrPres-like protease-resistant banding profile. These fibrils induced the formation of PrPresdeposits in transgenic mice coexpressing wt and GPI-anchorless PrPC(wt/GPI−) at a combined level comparable to that of PrPCexpression in wt mice. Secondary passage into mice expressing wt, GPI−, or wt plus GPI−PrPCinduced TSE disease with novel clinical, histopathological, and biochemical phenotypes. Contrary to laboratory-adapted mouse scrapie strains, the synthetic prion agents exhibited a preference for conversion of GPI−PrPCand, in one case, caused disease only in GPI−mice. Our data show that novel TSE agents can be generatedde novosolely from purified mouse rPrP after amplification in mice coexpressing normal levels of wt and anchorless PrPC. These observations provide insight into the minimal elements required to create prionsin vitroand suggest that the PrPCGPI anchor can modulate the propagation of synthetic TSE strains.
