AIMS The amino acid sequence of prion protein (PrP) is a key determinant in the transmissibility of prion diseases. While PrP sequence is highly conserved among mammalian species, minor changes in the PrP amino acid sequence may confer alterations in the transmissibility of prion diseases. Classical bovine spongiform encephalopathy (C-BSE) is the only zoonotic prion strain reported to date causing variant Creutzfeldt-Jacob disease (vCJD) in humans, although experimental transmission points to atypical L-BSE and some classical scrapie isolates as also zoonotic. The precise molecular elements in the human PrP sequence that limit the transmissibility of prion strains such as sheep/goat scrapie or cervid chronic wasting disease (CWD) are not well known. METHODS The transmissibility of a panel of diverse prions from different species was compared in transgenic mice expressing either wild type human-PrPC (MDE-HuTg340) or a mutated human PrPC harbouring Val166 -Gln168 amino acid changes (VDQ-HuTg372) in the b2-a2 loop instead of Met166 -Glu168 wild type variants. RESULTS VDQ-HuTg372 mice were more susceptible to prions than MDE-HuTg340 mice in a strain-dependent manner. CONCLUSIONS Met166 -Glu168 amino acid residues present in wild type human PrPC are molecular determinants that limit the propagation of most prion strains assayed in the human PrP context.

中文翻译：

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人类 PrP β2-α2 环中的 Met 166-Glu 168 残基解释了对朊病毒感染的进化抗性

目的 朊病毒蛋白（PrP）的氨基酸序列是朊病毒疾病传播的关键决定因素。虽然 PrP 序列在哺乳动物物种中高度保守，但 PrP 氨基酸序列的微小变化可能会导致朊病毒疾病传播能力的改变。经典牛海绵状脑病 (C-BSE) 是迄今为止报道的唯一一种人畜共患病朊病毒株，可导致人类变异的克雅氏病 (vCJD)，尽管实验传播表明非典型 L-BSE 和一些经典的瘙痒病分离株也是人畜共患病的。人类 PrP 序列中限制朊病毒株如绵羊/山羊痒病或宫颈慢性消耗性疾病 (CWD) 传播的精确分子元件尚不为人所知。方法 在表达野生型人-PrPC (MDE-HuTg340) 或在 b2- a2 环而不是 Met166 -Glu168 野生型变体。结果 VDQ-HuTg372 小鼠比 MDE-HuTg340 小鼠更易感染朊病毒，且呈菌株依赖性。结论存在于野生型人PrPC中的Met166-Glu168氨基酸残基是限制在人PrP环境中测定的大多数朊病毒株繁殖的分子决定因素。结果 VDQ-HuTg372 小鼠比 MDE-HuTg340 小鼠更易感染朊病毒，且呈菌株依赖性。结论存在于野生型人PrPC中的Met166-Glu168氨基酸残基是限制在人PrP环境中测定的大多数朊病毒株繁殖的分子决定因素。结果 VDQ-HuTg372 小鼠比 MDE-HuTg340 小鼠更易感染朊病毒，且呈菌株依赖性。结论存在于野生型人PrPC中的Met166-Glu168氨基酸残基是限制在人PrP环境中测定的大多数朊病毒株繁殖的分子决定因素。