Charco Jorge M, Eraña Hasier, Venegas Vanessa, García-Martínez Sandra, López-Moreno Rafael, González-Miranda Ezequiel, Pérez-Castro Miguel Ángel, Castilla Joaquín
CIC bioGUNE, Parque Tecnológico de Bizkaia, 48160 Derio, Spain.
IKERBASQUE, Basque Foundation for Science, 48011 Bilbao, Spain.
Pathogens. 2017 Dec 14;6(4):67. doi: 10.3390/pathogens6040067.
The misfolding of the cellular prion protein (PrP) into the disease-associated isoform (PrP) and its accumulation as amyloid fibrils in the central nervous system is one of the central events in transmissible spongiform encephalopathies (TSEs). Due to the proteinaceous nature of the causal agent the molecular mechanisms of misfolding, interspecies transmission, neurotoxicity and strain phenomenon remain mostly ill-defined or unknown. Significant advances were made using in vivo and in cellula models, but the limitations of these, primarily due to their inherent complexity and the small amounts of PrP that can be obtained, gave rise to the necessity of new model systems. The production of recombinant PrP using and subsequent induction of misfolding to the aberrant isoform using different techniques paved the way for the development of cell-free systems that complement the previous models. The generation of the first infectious recombinant prion proteins with identical properties of brain-derived PrP increased the value of cell-free systems for research on TSEs. The versatility and ease of implementation of these models have made them invaluable for the study of the molecular mechanisms of prion formation and propagation, and have enabled improvements in diagnosis, high-throughput screening of putative anti-prion compounds and the design of novel therapeutic strategies. Here, we provide an overview of the resultant advances in the prion field due to the development of recombinant PrP and its use in cell-free systems.
细胞朊蛋白（PrP）错误折叠成与疾病相关的异构体（PrP），并以淀粉样原纤维的形式在中枢神经系统中积累，是传染性海绵状脑病（TSEs）的核心事件之一。由于病原体的蛋白质性质，错误折叠、种间传播、神经毒性和毒株现象的分子机制大多仍不明确或未知。利用体内和细胞内模型取得了重大进展，但这些模型的局限性，主要是由于其固有的复杂性以及可获得的PrP量少，导致需要新的模型系统。利用[具体方法]生产重组PrP，并随后使用不同技术将其错误折叠诱导为异常异构体，为开发补充先前模型的无细胞系统铺平了道路。首个具有与脑源性PrP相同特性的传染性重组朊蛋白的产生，提高了无细胞系统在TSEs研究中的价值。这些模型的多功能性和易于实施，使其在朊病毒形成和传播的分子机制研究中具有不可估量的价值，并有助于改进诊断、高通量筛选潜在的抗朊病毒化合物以及设计新的治疗策略。在此，我们概述了由于重组PrP的开发及其在无细胞系统中的应用，朊病毒领域所取得的进展。
