Barrio Tomás, Douet Jean-Yves, Žáková Dana, Eraña Hasier, Huor Alvina, Cassard Hervé, Alzuguren Oihane, Lugan Séverine, Aron Naïma, Péran Patrice, Castilla Joaquín, Andréoletti Olivier
UMR INRAE-ENVT 1225, Interactions Hôtes-Agents Pathogènes, Ecole Nationale Vétérinaire de Toulouse, 23 Chemin des Capelles, 31076, Toulouse, France.
Department of Prion Diseases, Slovak Medical University, Bratislava, Slovakia.
Acta Neuropathol. 2025 Jun 16;149(1):62. doi: 10.1007/s00401-025-02903-5.
The mutation E200K in the prion protein gene (PRNP) is the most common variant in genetic Creutzfeldt-Jakob disease (gCJD). The clinical and pathological features observed in patients with E200K gCJD led to the hypothesis that the prion strains responsible for this form of the disease may be related to those involved in sporadic CJD (sCJD). In this study, we characterized the prion strains responsible for E200K gCJD cases from Slovakia (n = 12), Spain (n = 9), and France (n = 3) using transgenic mouse models expressing human prion protein (PrP). The cohort included patients with various PRNP genotypes: E200K-Met/Met, E200K-Met/E200K-Met, E200K-Met/Val, and E200K-Val/Val. Prion strain characterization revealed that the strains isolated from E200K gCJD cases corresponded to the two most common strains identified in sCJD cases: M1 and V2. Depending on the individual, these strains were either present as pure M1 or V2, or as a mixture of both (M1 + V2). Additionally, peripheral tissues from E200K-Met/Met patients (n = 4) and one E200K-Met/Val case were analyzed for prion infectivity and seeding activity. Similar to sCJD patients, low but detectable levels of prions were found in various peripheral tissues of E200K gCJD cases. Overall, our findings suggest that the prion strains and their distribution in the body are highly similar between E200K gCJD and sCJD patients. These similarities indicate that individuals carrying the E200K mutation may serve as a valuable model for understanding CJD pathogenesis during the preclinical phase of the disease.
朊病毒蛋白基因（PRNP）中的E200K突变是遗传性克雅氏病（gCJD）中最常见的变异。E200K gCJD患者所观察到的临床和病理特征引发了这样一种假说，即导致这种疾病形式的朊病毒株可能与散发性克雅氏病（sCJD）中涉及的毒株有关。在本研究中，我们使用表达人朊病毒蛋白（PrP）的转基因小鼠模型，对来自斯洛伐克（n = 12）、西班牙（n = 9）和法国（n = 3）的E200K gCJD病例所对应的朊病毒株进行了特征分析。该队列包括具有各种PRNP基因型的患者：E200K-Met/Met、E200K-Met/E200K-Met、E200K-Met/Val和E200K-Val/Val。朊病毒株特征分析表明，从E200K gCJD病例中分离出的毒株对应于在sCJD病例中鉴定出的两种最常见的毒株：M1和V2。根据个体情况，这些毒株要么以纯M1或V2形式存在，要么以两者的混合物（M1 + V2）形式存在。此外，对E200K-Met/Met患者（n = 4）和1例E200K-Met/Val病例的外周组织进行了朊病毒感染性和种子活性分析。与sCJD患者相似，在E200K gCJD病例的各种外周组织中发现了低但可检测水平的朊病毒。总体而言，我们的研究结果表明，E200K gCJD和sCJD患者之间的朊病毒株及其在体内的分布高度相似。这些相似性表明，携带E200K突变的个体可能是在疾病临床前期阶段理解CJD发病机制的有价值模型。
