One of remarkable features of sporadic Creutzfeldt-Jakob disease (sCJD) is the great phenotypic variability. Understanding the molecular basis of this variability has important implications for the development of therapeutic approaches. It is well established that, in many cases, phenotypic heterogeneity of sCJD is under control of two determinants: the genotype at the methionine (M)/valine (V) polymorphic codon 129 of the human prion protein gene and the type, 1 or 2, of the pathogenic and disease-related form of the prion protein, PrPD. However, this scenario fails to explain the existence of distinct heterozygous sCJDMV2 subtypes, where heterogeneity occurs without any variation of the 129 allotype and PrPD type. One of these subtypes, denoted sCJDMV2C, associated with PrPD type 2, is characterized by widespread spongiform degeneration of the cerebral cortex (C). The second variant, denoted sCJDMV2K, features prominent deposition of PrPD amyloid forming kuru type (K) plaques. Here we used a mass spectrometry based approach to test the hypothesis that phenotypic variability within the sCJDMV2 subtype is at least partly determined by the abundance of 129 M and 129 V polymorphic forms of proteinase K-resistant PrPD (resPrPD). Consistent with this hypothesis, our data demonstrated a strong correlation of the MV2C and MV2K phenotypes with the relative populations of protease-resistant forms of the pathogenic prion proteins, resPrPD-129 M and resPrPD-129 V, where resPrPD-129 M dominated in the sCJDMV2C variant and resPrPD-129 V in the sCJDMV2K variant. This finding suggests an important, previously unrecognized mechanism for phenotypic determination in human prion diseases.

中文翻译：

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克雅氏病表型异质性的新机制。

散发性克雅氏病 (sCJD) 的显着特征之一是巨大的表型变异性。了解这种变异性的分子基础对治疗方法的发展具有重要意义。已经确定，在许多情况下，sCJD 的表型异质性受两个决定因素的控制：人类朊病毒蛋白基因的甲硫氨酸 (M)/缬氨酸 (V) 多态性密码子 129 的基因型和类型，1 或 2 ，致病和疾病相关形式的朊病毒蛋白，PrPD。然而，这种情况无法解释不同杂合子 sCJDMV2 亚型的存在，其中异质性发生而没有 129 同种异体和 PrPD 类型的任何变异。这些亚型之一，表示为 sCJDMV2C，与 2 型 PrPD 相关，其特征是大脑皮层广泛海绵状变性 (C)。第二种变体表示为 sCJDMV2K，其特征是 PrPD 淀粉样蛋白显着沉积，形成 kuru 型 (K) 斑块。在这里，我们使用基于质谱的方法来检验 sCJDMV2 亚型内的表型变异性至少部分由蛋白酶 K 抗性 PrPD (resPrPD) 的 129 M 和 129 V 多态性形式的丰度决定的假设。与这一假设一致，我们的数据表明 MV2C 和 MV2K 表型与致病性朊病毒蛋白 resPrPD-129 M 和 resPrPD-129 V 的蛋白酶抗性形式的相对群体之间存在很强的相关性，其中 resPrPD-129 M 在sCJDMV2C 变体和 sCJDMV2K 变体中的 resPrPD-129 V。这一发现表明一个重要的，