Prusiner S B
Department of Neurology, University of California, San Francisco.
Arch Neurol. 1993 Nov;50(11):1129-53. doi: 10.1001/archneur.1993.00540110011002.
Enriching fractions from Syrian hamster (SHa) brain for scrapie prion infectivity led to the discovery of the prion protein (PrP). Prion diseases include scrapie of sheep and bovine spongiform encephalopathy of cattle as well as Creutzfeldt-Jakob disease (CJD) and Gerstmann-Sträussler-Scheinker syndrome (GSS) of humans. Transgenic (Tg) mice expressing both SHa and mouse (Mo) PrP genes were used to probe the molecular basis of the species barrier and the mechanism of scrapie prion replication. Bioassays of brain extracts from two scrapie-infected Tg lines showed that the prion inoculum determines that prions are synthesized de novo, even though the cells express both PrP genes. Studies with artificial prions produced from chimeric Mo/SHaPrP transgenes underscore the concept that inoculated prion dictates which prion will be replicated. Discovery of mutations in the PrP genes of humans with GSS and familial CJD established that prion diseases are both genetic and infectious. Transgenic mice expressing high levels of MoPrP-P101L, corresponding to the GSS point mutation (P102L) in human PrP, spontaneously develop neurologic dysfunction, spongiform degeneration, and astrocytic gliosis. Inoculation of brain extracts prepared from these Tg (MoPrP-P101L) mice produced neurodegeneration in recipient animals after prolonged incubation times. These results are in accord with those of other studies and argue that prions are devoid of foreign nucleic acid. Structural investigations of cellular prion protein (PrPC) and prion protein scrapie (PrPSc) suggest that the difference may be conformational. Conditions that diminished the beta-sheet content of PrPSc were the same as those identified previously that inactivate prion infectivity. Whether prion diversity as reflected by distinct "strains" producing different patterns of PrPSc accumulation is due to different conformers of PrPSc remains to be established. Advances in the purification and characterization of both PrPC and PrPSc seem to have identified the central event in PrPSc synthesis and prion propagation, ie, the unfolding of PrPC followed by its refolding into PrPSc. These findings underscore the fundamental features of prion structure and propagation that differentiate prions from other transmissible pathogens.
从叙利亚仓鼠（SHa）脑中富集具有瘙痒病朊病毒感染性的组分，从而发现了朊病毒蛋白（PrP）。朊病毒疾病包括绵羊瘙痒病、牛海绵状脑病以及人类的克雅氏病（CJD）和格斯特曼-施特劳斯勒-谢inker综合征（GSS）。表达SHa和小鼠（Mo）PrP基因的转基因（Tg）小鼠被用于探究物种屏障的分子基础以及瘙痒病朊病毒复制的机制。对两个感染瘙痒病的Tg品系脑提取物的生物测定表明，尽管细胞同时表达两种PrP基因，但朊病毒接种物决定了朊病毒是从头合成的。对由嵌合Mo/SHaPrP转基因产生的人工朊病毒的研究强调了这样一个概念，即接种的朊病毒决定了哪种朊病毒将被复制。在患有GSS和家族性CJD的人类PrP基因中发现突变，证实了朊病毒疾病既是遗传性的又是传染性的。表达高水平MoPrP-P101L（对应于人类PrP中的GSS点突变P102L）的转基因小鼠会自发出现神经功能障碍、海绵状变性和星形胶质细胞增生。用这些Tg（MoPrP-P101L）小鼠制备的脑提取物进行接种，在长时间孵育后会使受体动物发生神经变性。这些结果与其他研究结果一致，表明朊病毒不含外源核酸。对细胞朊病毒蛋白（PrPC）和瘙痒病朊病毒蛋白（PrPSc）的结构研究表明，差异可能在于构象。降低PrPScβ-折叠含量的条件与先前确定的使朊病毒感染性失活的条件相同。由产生不同PrPSc积累模式的不同“毒株”所反映的朊病毒多样性是否归因于PrPSc的不同构象仍有待确定。PrPC和PrPSc纯化及表征方面的进展似乎已经确定了PrPSc合成和朊病毒传播的核心事件，即PrPC的解折叠，随后重新折叠成PrPSc。这些发现强调了朊病毒结构和传播的基本特征，这些特征将朊病毒与其他可传播病原体区分开来。
