Scrapie susceptibility-linked polymorphisms modulate the in vitro conversion of sheep prion protein to protease-resistant forms
Scrapie susceptibility-linked polymorphisms modulate the in vitro conversion of sheep prion protein to protease-resistant forms
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DOI：
10.1073/pnas.94.10.4931
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发表时间：
1997-05-13
影响因子：
11.1
通讯作者：
Smits, MA
中科院分区：
文献类型：
--
作者：
Bossers, A;Belt, PBGM;Smits, MA
朊病毒病是人类和动物的自然传播的神经退行性疾病。它们的特征在于主要在中枢神经系统中积累宿主编码的细胞朊病毒蛋白（PrPC）的蛋白酶抗性瘙痒症相关朊病毒蛋白（PrPSc）。PrP基因的多态性与朊病毒疾病易感性的差异有关。这些影响的机制仍然未知。在这里，我们描述了绵羊PrP基因多态性的影响的研究转化成蛋白酶抗性形式的PrPC。在无细胞系统中，绵羊Prp（Sc）诱导绵羊PrPC转化为与PrPSc相似或相同的蛋白酶抗性PrP（PrP res）。在PrPC或PrPSc中存在的多态性对无细胞转化效率有显著影响。与高敏感性羊瘙痒症和短的生存时间的羊瘙痒症感染的PrP变异体被有效地转换成PrP-res。与中性的敏感性和中间的生存时间的野生型PrP变异体转换与中间的效率。与羊瘙痒病抗性和长存活时间相关的PrP变异转化较差。因此，在体外转换特性的羊朊蛋白变异体反映了他们的链接与羊瘙痒症的易感性和生存时间的羊瘙痒症。PrPC和PrPSc的多态性对无细胞转化特性的调节作用表明，除了物种障碍外，多态性障碍在朊病毒疾病的传播中起着重要作用。
Prion diseases are natural transmissible neurodegenerative disorders in humans and animals. They are characterized by the accumulation of a protease-resistant scrapie-associated prion protein (PrPSc) of the host-encoded cellular prion protein (PrPC) mainly in the central nervous system. Polymorphisms in the PrP gene are linked to differences in susceptibility for prion diseases. The mechanisms underlying these effects are still unknown. Here we describe studies of the influence of sheep PrP polymorphisms on the conversion of PrPC into protease-resistant forms. In a cell-free system, sheep Prp(Sc) induced the conversion of sheep PrPC into protease-resistant PrP (PrP res) similar or identical to PrPSc. Polymorphisms present in either PrPC or PrPSc had dramatic effects on the cell-free conversion efficiencies. The PrP variant associated with a high susceptibility to scrapie and short survival times of scrapie-affected sheep was efficiently converted into PrP-res. The wild-type PrP variant associated with a neutral effect on susceptibility and intermediate survival times was converted with intermediate efficiency. The PrP variant associated with scrapie resistance and long survival times was poorly converted. Thus the in vitro conversion characteristics of the sheep PrP variants reflect their linkage with scrapie susceptibility and survival times of scrapie-affected sheep. The modulating effect of the polymorphisms in PrPC and PrPSc on the cell-free conversion characteristics suggests that, besides the species barrier, polymorphism barriers play a significant role in the transmissibility of prion diseases.