Pérez-Castro Miguel Ángel, Eraña Hasier, Vidal Enric, Charco Jorge M, Lorenzo Nuria L, Gonçalves-Anjo Nuno, Galarza-Ahumada Josu, Díaz-Domínguez Carlos M, Piñeiro Patricia, González-Miranda Ezequiel, Giler Samanta, Telling Glenn, Sánchez-Martín Manuel A, Garrido Joseba, Geijo Mariví, Requena Jesús R, Castilla Joaquín
Center for Cooperative Research in Biosciences (CIC BioGUNE), Basque Research and Technology Alliance (BRTA), Derio, Spain.
Centro de Investigación Biomédica en Red de Enfermedades infecciosas (CIBERINFEC), Carlos III National Health Institute, Madrid, Spain.
PLoS Pathog. 2025 Jan 22;21(1):e1012890. doi: 10.1371/journal.ppat.1012890. eCollection 2025 Jan.
Prion diseases, particularly sporadic cases, pose a challenge due to their complex nature and heterogeneity. The underlying mechanism of the spontaneous conversion from PrPC to PrPSc, the hallmark of prion diseases, remains elusive. To shed light on this process and the involvement of cofactors, we have developed an in vitro system that faithfully mimics spontaneous prion misfolding using minimal components. By employing this PMSA methodology and introducing an isoleucine residue at position 108 in mouse PrP, we successfully generated recombinant murine prion strains with distinct biochemical and biological properties. Our study aimed to explore the influence of a polyanionic cofactor in modulating strain selection and infectivity in de novo-generated synthetic prions. These results not only validate PMSA as a robust method for generating diverse bona fide recombinant prions but also emphasize the significance of cofactors in shaping specific prion conformers capable of crossing species barriers. Interestingly, once these conformers are established, our findings suggest that cofactors are not necessary for their infectivity. This research provides valuable insights into the propagation and maintenance of the pathobiological features of cross-species transmissible recombinant murine prion and highlights the intricate interplay between cofactors and prion strain characteristics.
朊病毒疾病，尤其是散发性病例，因其性质复杂和异质性而构成挑战。从正常朊蛋白（PrPC）自发转化为致病性朊蛋白（PrPSc）这一朊病毒疾病的标志，其潜在机制仍不清楚。为了阐明这一过程以及辅助因子的作用，我们开发了一种体外系统，该系统使用最少的成分忠实地模拟朊病毒的自发错误折叠。通过采用这种PMSA方法，并在小鼠朊蛋白的第108位引入异亮氨酸残基，我们成功地产生了具有不同生化和生物学特性的重组小鼠朊病毒株。我们的研究旨在探讨一种聚阴离子辅助因子在调节新生合成朊病毒的毒株选择和感染性方面的影响。这些结果不仅验证了PMSA作为一种生成多种真正重组朊病毒的可靠方法，还强调了辅助因子在塑造能够跨越物种屏障的特定朊病毒构象方面的重要性。有趣的是，一旦这些构象形成，我们的研究结果表明辅助因子对其感染性并非必需。这项研究为跨物种传播的重组小鼠朊病毒的病理生物学特征的传播和维持提供了有价值的见解，并突出了辅助因子与朊病毒株特征之间复杂的相互作用。
