Moore Roger A, Head Mark W, Ironside James W, Ritchie Diane L, Zanusso Gianluigi, Choi Young Pyo, Priola Suzette A
Rocky Mountain Laboratories, National Institute of Allergy & Infectious Diseases, National Institutes of Health, Hamilton, Montana, United States of America.
National CJD Research & Surveillance Unit, Centre for Clinical Brain Sciences, School of Clinical Sciences, University of Edinburgh, Edinburgh, United Kingdom.
PLoS Pathog. 2016 Feb 3;12(2):e1005416. doi: 10.1371/journal.ppat.1005416. eCollection 2016 Feb.
Sporadic Creutzfeldt-Jakob disease (sCJD) is the most prevalent of the human prion diseases, which are fatal and transmissible neurodegenerative diseases caused by the infectious prion protein (PrP(Sc)). The origin of sCJD is unknown, although the initiating event is thought to be the stochastic misfolding of endogenous prion protein (PrP(C)) into infectious PrP(Sc). By contrast, human growth hormone-associated cases of iatrogenic CJD (iCJD) in the United Kingdom (UK) are associated with exposure to an exogenous source of PrP(Sc). In both forms of CJD, heterozygosity at residue 129 for methionine (M) or valine (V) in the prion protein gene may affect disease phenotype, onset and progression. However, the relative contribution of each PrP(C) allotype to PrP(Sc) in heterozygous cases of CJD is unknown. Using mass spectrometry, we determined that the relative abundance of PrP(Sc) with M or V at residue 129 in brain specimens from MV cases of sCJD was highly variable. This result is consistent with PrP(C) containing an M or V at residue 129 having a similar propensity to misfold into PrP(Sc) thus causing sCJD. By contrast, PrP(Sc) with V at residue 129 predominated in the majority of the UK human growth hormone associated iCJD cases, consistent with exposure to infectious PrP(Sc) containing V at residue 129. In both types of CJD, the PrP(Sc) allotype ratio had no correlation with CJD type, age at clinical onset, or disease duration. Therefore, factors other than PrP(Sc) allotype abundance must influence the clinical progression and phenotype of heterozygous cases of CJD.
散发性克雅氏病（sCJD）是最常见的人类朊病毒病，这类疾病是由传染性朊病毒蛋白（PrP(Sc)）引起的致命性、可传播的神经退行性疾病。尽管人们认为起始事件是内源性朊病毒蛋白（PrP(C)）随机错误折叠为传染性PrP(Sc)，但sCJD的起源尚不清楚。相比之下，英国与人类生长激素相关的医源性克雅氏病（iCJD）病例与接触外源性PrP(Sc)有关。在两种形式的克雅氏病中，朊病毒蛋白基因第129位密码子的甲硫氨酸（M）或缬氨酸（V）杂合性可能会影响疾病表型、发病和进展。然而，在克雅氏病杂合病例中，每种PrP(C)同种异型对PrP(Sc)的相对贡献尚不清楚。我们通过质谱法测定，在sCJD的MV型病例的脑标本中，第129位密码子带有M或V的PrP(Sc)相对丰度高度可变。这一结果与第129位密码子含有M或V的PrP(C)具有相似的错误折叠为PrP(Sc)从而导致sCJD的倾向一致。相比之下，在大多数英国与人类生长激素相关的iCJD病例中第129位密码子带有V的PrP(Sc)占主导，这与接触第129位密码子含有V的传染性PrP(Sc)一致。在两种类型的克雅氏病中，PrP(Sc)同种异型比例与克雅氏病类型、临床发病年龄或病程均无相关性。因此，除PrP(Sc)同种异型丰度外的其他因素必定会影响克雅氏病杂合病例的临床进展和表型。
