PDF(Pubmed)
Abstract：
Most cases of human prion disease arise due to spontaneous misfolding of WT or mutant prion protein, yet recapitulating this event in animal models has proven challenging. It remains unclear whether spontaneous prion generation can occur within the mouse lifespan in the absence of protein overexpression and how disease-causing mutations affect prion strain properties. To address these issues, we generated knockin mice that express the misfolding-prone bank vole prion protein (BVPrP). While mice expressing WT BVPrP (I109 variant) remained free from neurological disease, a subset of mice expressing BVPrP with mutations (D178N or E200K) causing genetic prion disease developed progressive neurological illness. Brains from spontaneously ill knockin mice contained prion disease-specific neuropathological changes as well as atypical protease-resistant BVPrP. Moreover, brain extracts from spontaneously ill D178N- or E200K-mutant BVPrP-knockin mice exhibited prion seeding activity and transmitted disease to mice expressing WT BVPrP. Surprisingly, the properties of the D178N- and E200K-mutant prions appeared identical before and after transmission, suggesting that both mutations guide the formation of a similar atypical prion strain. These findings imply that knockin mice expressing mutant BVPrP spontaneously develop a bona fide prion disease and that mutations causing prion diseases may share a uniform initial mechanism of action.
摘要：
大多数人类朊病毒疾病的病例是由于WT或突变型朊病毒蛋白的自发错误折叠引起的，然而，在动物模型中重述这一事件已被证明具有挑战性。目前尚不清楚在没有蛋白质过表达的情况下，自发性朊病毒的产生是否可以在小鼠寿命内发生，以及致病突变如何影响朊病毒株的特性。为了解决这些问题,我们产生了表达易发生错误折叠的库田鼠朊病毒蛋白（BVPrP）的敲入小鼠。虽然表达WTBVPrP（I109变体）的小鼠没有神经系统疾病，引起遗传性朊病毒病的表达BVPrP突变(D178N或E200K)的小鼠亚组发展为进行性神经系统疾病.来自自发性患病敲入小鼠的大脑含有朊病毒疾病特异性神经病理学变化以及非典型蛋白酶抗性BVPrP。此外，来自自发性疾病D178N-或E200K-突变型BVPrP敲入小鼠的脑提取物表现出朊病毒接种活性，并将疾病传播给表达WTBVPrP的小鼠。令人惊讶的是,D178N-和E200K-突变型病毒的性质在传播之前和之后出现了相同的，这表明这两种突变都指导了类似的非典型朊病毒株的形成。这些发现表明，表达突变型BVPrP的敲入小鼠会自发地发展出真正的朊病毒病，并且引起朊病毒疾病的突变可能具有统一的初始作用机制。
