Inherited prion diseases are caused by autosomal dominant coding mutations in the human prion protein (PrP) gene (PRNP) and account for about 15% of human prion disease cases worldwide. The proposed mechanism is that the mutation predisposes to conformational change in the expressed protein, leading to the generation of disease-related multichain PrP assemblies that propagate by seeded protein misfolding. Despite considerable experimental support for this hypothesis, to-date spontaneous formation of disease-relevant, transmissible PrP assemblies in transgenic models expressing only mutant human PrP has not been demonstrated. Here, we report findings from transgenic mice that express human PrP 117V on a mouse PrP null background (117VV Tg30 mice), which model the PRNP A117V mutation causing inherited prion disease (IPD) including Gerstmann-Sträussler-Scheinker (GSS) disease phenotypes in humans. By studying brain samples from uninoculated groups of mice, we discovered that some mice (≥475 days old) spontaneously generated abnormal PrP assemblies, which after inoculation into further groups of 117VV Tg30 mice, produced a molecular and neuropathological phenotype congruent with that seen after transmission of brain isolates from IPD A117V patients to the same mice. To the best of our knowledge, the 117VV Tg30 mouse line is the first transgenic model expressing only mutant human PrP to show spontaneous generation of transmissible PrP assemblies that directly mirror those generated in an inherited prion disease in humans.

病毒遗传病是由人类病毒蛋白（PrP）基因（PRNP）中的常染色体显性编码突变引起的，约占全世界worldwide病毒疾病病例的15％。所提出的机制是该突变易于使表达的蛋白质发生构象变化，从而导致疾病相关的多链PrP装配的产生，该装配通过种子蛋白错误折叠而传播。尽管对此假说有相当多的实验支持，但迄今尚未证明在仅表达突变型人PrP的转基因模型中疾病相关的可传播PrP组装体的自发形成。在这里，我们报告了从在小鼠PrP无效背景上表达人PrP 117V的转基因小鼠（117VV Tg30小鼠）的发现，该模型模拟了PRNPA117V突变会导致人类遗传性病毒病（IPD），包括Gerstmann-Sträussler-Scheinker（GSS）疾病表型。通过研究未接种小鼠组的脑样本，我们发现一些小鼠（≥475天大）自发产生异常的PrP装配，将其接种到其他117VV Tg30小鼠组中后，产生了与传播后可见的分子和神经病理学表型从IPD A117V患者到同一只小鼠的脑分离株的分离。据我们所知，117VV Tg30小鼠品系是第一个仅表达突变型人类PrP的转基因模型，显示出自发产生的可传播PrP装配，可直接反映人类遗传性病毒疾病中产生的装配。