Clarke A R, Jackson G S, Collinge J
Medical Research Council Prion Unit, Department of Neurogenetics, Imperial College School of Medicine at St Mary's, London W2 1NY, UK.
Philos Trans R Soc Lond B Biol Sci. 2001 Feb 28;356(1406):185-95. doi: 10.1098/rstb.2000.0764.
Prion diseases such as Creutzfeldt-Jakob disease (CJD) in humans and scrapie and bovine spongiform encephalopathy (BSE) in animals are associated with the accumulation in affected brains of a conformational isomer (PrP(Sc)) of host-derived prion protein (PrP(C)). According to the protein-only hypothesis, PrP(Sc) is the principal or sole component of transmissible prions. The conformational change known to be central to prion propagation, from a predominantly alpha-helical fold to one predominantly comprising beta structure, can now be reproduced in vitro, and the ability of beta-PrP to form fibrillar aggregates provides a plausible molecular mechanism for prion propagation. The existence of multiple prion strains has been difficult to explain in terms of a protein-only infectious agent but recent studies of human prion diseases suggest that strain-specific phenotypes can be encoded by different PrP conformations and glycosylation patterns. The experimental confirmation that a novel form of human prion disease, variant CJD, is caused by the same prion strain as cattle BSE, has highlighted the pressing need to understand the molecular basis of prion propagation and the transmission barriers that limit their passage between mammalian species. These and other advances in the fundamental biology of prion propagation are leading to strategies for the development of rational therapeutics.
诸如人类克雅氏病（CJD）以及动物的羊瘙痒症和牛海绵状脑病（BSE）等朊病毒疾病，与宿主来源的朊病毒蛋白（PrP(C)）的一种构象异构体（PrP(Sc)）在受影响大脑中的积累有关。根据仅蛋白质假说，PrP(Sc)是传染性朊病毒的主要或唯一成分。已知对朊病毒传播至关重要的构象变化，即从主要为α螺旋折叠转变为主要包含β结构，现在可以在体外重现，并且β-PrP形成纤维状聚集体的能力为朊病毒传播提供了一种合理的分子机制。就仅蛋白质感染因子而言，多种朊病毒株的存在一直难以解释，但最近对人类朊病毒疾病的研究表明，毒株特异性表型可由不同的PrP构象和糖基化模式编码。新型人类朊病毒疾病——变异型克雅氏病，由与牛BSE相同的朊病毒株引起，这一实验证实突出了迫切需要了解朊病毒传播的分子基础以及限制其在哺乳动物物种间传播的传播障碍。朊病毒传播基础生物学的这些以及其他进展正引领着合理治疗方法开发的策略。
