Bessen R A, Kocisko D A, Raymond G J, Nandan S, Lansbury P T, Caughey B
Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, Hamilton, Montana 59840, USA.
Nature. 1995 Jun 22;375(6533):698-700. doi: 10.1038/375698a0.
The infectious agents causing scrapie and other transmissible spongiform encephalopathies have been postulated to consist solely of the protease-resistant form of prion protein (PrPSc). One unprecedented requirement of the protein-only model is that the 'inheritance' of pathogen strain differences must be mediated by stable variations in PrPSc structure, rather than mutations in an agent-specific nucleic acid. Strain differences in PrPSc structure have been described for the hyper (HY) and drowsy (DY) strains of hamster transmissible mink encephalopathy (TME), a scrapie-like disease originating in mink. Although HY and DY PrPSc are both post-translationally derived from the precursor prion protein (PrPC) they are cleaved at different amino-terminal sites by proteinase K (ref. 8). Here we investigate whether this strain-specific property of PrPSc is transmitted to PrPC during formation of new PrPSc. PrPSc from the HY and DY TME strains converted the protease-sensitive PrPC into two distinct sets of protease-resistant PrP products in a cell-free system. These data provide evidence that self-propagation of PrPSc polymers with distinct three-dimensional structures could be the molecular basis of scrapie strains.
引发羊瘙痒症及其他传染性海绵状脑病的感染因子据推测仅由抗蛋白酶形式的朊病毒蛋白（PrPSc）构成。仅蛋白质模型的一个前所未有的要求是，病原体毒株差异的“遗传”必须由PrPSc结构的稳定变异介导，而非由特定病原体核酸的突变介导。对于仓鼠传染性水貂脑病（TME）的高毒株（HY）和嗜睡株（DY），已描述了PrPSc结构上的毒株差异，TME是一种起源于水貂的类羊瘙痒症疾病。尽管HY和DY PrPSc均在翻译后从前体朊病毒蛋白（PrPC）衍生而来，但它们被蛋白酶K在不同的氨基末端位点切割（参考文献8）。在此，我们研究PrPSc的这种毒株特异性特性在新PrPSc形成过程中是否会传递给PrPC。来自HY和DY TME毒株的PrPSc在无细胞系统中将蛋白酶敏感的PrPC转化为两组不同的抗蛋白酶PrP产物。这些数据提供了证据，表明具有不同三维结构的PrPSc聚合物的自我增殖可能是羊瘙痒症毒株的分子基础。
