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.
Nat Commun. 2024 Mar 8;15(1):2112. doi: 10.1038/s41467-024-46360-2.
Prion diseases are a group of rapidly progressing neurodegenerative disorders caused by the misfolding of the endogenous prion protein (PrP) into a pathogenic form (PrP). This process, despite being the central event underlying these disorders, remains largely unknown at a molecular level, precluding the prediction of new potential outbreaks or interspecies transmission incidents. In this work, we present a method to generate bona fide recombinant prions de novo, allowing a comprehensive analysis of protein misfolding across a wide range of prion proteins from mammalian species. We study more than 380 different prion proteins from mammals and classify them according to their spontaneous misfolding propensity and their conformational variability. This study aims to address fundamental questions in the prion research field such as defining infectivity determinants, interspecies transmission barriers or the structural influence of specific amino acids and provide invaluable information for future diagnosis and therapy applications.
朊病毒病是一组由内源性朊病毒蛋白（PrP）错误折叠成致病性形式（PrP）引起的快速进展性神经退行性疾病。尽管这一过程是这些疾病的核心事件，但在分子水平上仍知之甚少，这使得我们无法预测新的潜在爆发或种间传播事件。在这项工作中，我们提出了一种从头开始生成真正重组朊病毒的方法，从而可以对来自哺乳动物的广泛范围的朊病毒蛋白的蛋白质错误折叠进行全面分析。我们研究了来自哺乳动物的 380 多种不同的朊病毒蛋白，并根据它们自发错误折叠的倾向和构象变异性对其进行分类。这项研究旨在解决朊病毒研究领域的一些基本问题，例如确定感染性决定因素、种间传播障碍或特定氨基酸的结构影响，并为未来的诊断和治疗应用提供宝贵的信息。
