Galeno Roberta, Di Bari Michele Angelo, Nonno Romolo, Cardone Franco, Sbriccoli Marco, Graziano Silvia, Ingrosso Loredana, Fiorini Michele, Valanzano Angelina, Pasini Giulia, Poleggi Anna, Vinci Ramona, Ladogana Anna, Puopolo Maria, Monaco Salvatore, Agrimi Umberto, Zanusso Gianluigi, Pocchiari Maurizio
Department of Neurosciences, Istituto Superiore di Sanità, Rome, Italy.
Department of Food Safety and Veterinary Public Health, Istituto Superiore di Sanità, Rome, Italy.
J Virol. 2017 May 12;91(11). doi: 10.1128/JVI.02390-16. Print 2017 Jun 1.
In 2007, we reported a patient with an atypical form of Creutzfeldt-Jakob disease (CJD) heterozygous for methionine-valine (MV) at codon 129 who showed a novel pathological prion protein (PrP) conformation with an atypical glycoform (AG) profile and intraneuronal PrP deposition. In the present study, we further characterize the conformational properties of this pathological prion protein (PrP MV), showing that PrP MV is composed of multiple conformers with biochemical properties distinct from those of PrP type 1 and type 2 of MV sporadic CJD (sCJD). Experimental transmission of CJD-MV to bank voles and gene-targeted transgenic mice carrying the human prion protein gene (TgHu mice) showed unique transmission rates, survival times, neuropathological changes, PrP deposition patterns, and PrP glycotypes that are distinct from those of sCJD-MV1 and sCJD-MV2. These biochemical and experimental data suggest the presence of a novel prion strain in CJD-MV Sporadic Creutzfeldt-Jakob disease is caused by the misfolding of the cellular prion protein, which assumes two different major conformations (type 1 and type 2) and, together with the methionine/valine polymorphic codon 129 of the prion protein gene, contribute to the occurrence of distinct clinical-pathological phenotypes. Inoculation in laboratory rodents of brain tissues from the six possible combinations of pathological prion protein types with codon 129 genotypes results in the identification of 3 or 4 strains of prions. We report on the identification of a novel strain of Creutzfeldt-Jakob disease isolated from a patient who carried an abnormally glycosylated pathological prion protein. This novel strain has unique biochemical characteristics, does not transmit to humanized transgenic mice, and shows exclusive transmission properties in bank voles. The identification of a novel human prion strain improves our understanding of the pathogenesis of the disease and of possible mechanisms of prion transmission.
2007年，我们报告了一名患有非典型克雅氏病（CJD）的患者，其朊蛋白基因第129密码子为蛋氨酸-缬氨酸（MV）杂合型，该患者表现出一种新型的病理性朊蛋白（PrP）构象，具有非典型糖型（AG）谱和神经元内PrP沉积。在本研究中，我们进一步表征了这种病理性朊蛋白（PrP MV）的构象特性，表明PrP MV由多种构象异构体组成，其生化特性不同于MV散发型克雅氏病（sCJD）的1型和2型PrP。将CJD-MV实验性传播给田鼠和携带人朊蛋白基因的基因靶向转基因小鼠（TgHu小鼠），显示出与sCJD-MV1和sCJD-MV2不同的独特传播率、存活时间、神经病理学变化、PrP沉积模式和PrP糖型。这些生化和实验数据表明CJD-MV中存在一种新型朊病毒株。散发型克雅氏病是由细胞朊蛋白错误折叠引起的，细胞朊蛋白呈现两种不同的主要构象（1型和2型），并且与朊蛋白基因的蛋氨酸/缬氨酸多态性第129密码子一起，导致不同临床病理表型的出现。将病理朊蛋白类型与第129密码子基因型的六种可能组合的脑组织接种到实验啮齿动物中，可鉴定出3种或4种朊病毒株。我们报告了从一名携带异常糖基化病理性朊蛋白的患者中分离出一种新型克雅氏病株。这种新型毒株具有独特的生化特性，不会传播给人源化转基因小鼠，并且在田鼠中显示出独特的传播特性。鉴定出一种新型人类朊病毒株有助于我们更好地理解该疾病的发病机制以及朊病毒传播的可能机制。
