Co-existence of scrapie prion protein types 1 and 2 in sporadic Creutzfeldt-Jakob disease: its effect on the phenotype and prion-type characteristics
Co-existence of scrapie prion protein types 1 and 2 in sporadic Creutzfeldt-Jakob disease: its effect on the phenotype and prion-type characteristics
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DOI：
10.1093/brain/awp196
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发表时间：
2009-10-01
期刊：
影响因子：
14.5
通讯作者：
Gambetti, Pierluigi
中科院分区：
文献类型：
--
作者：
Cali, Ignazio;Castellani, Rudolph;Gambetti, Pierluigi
根据朊蛋白（PrP）基因密码子129的蛋氨酸/缬氨酸多态性基因型和鉴定为1和2的两种蛋白酶k抗性痒病朊蛋白（PrPSc）类型中的任何一种的存在，在散发性克雅氏病（sCJD）中鉴定出五种表型不同的亚型。很长一段时间以来，人们已经知道两种PrPSc类型在同一病例中罕见地共存。最近，有报道称，使用类型特异性抗体，PrPSc 1型存在于所有携带PrPSc 2型的sCJD病例中。两种PrPSc类型的一致共存使sCJD的诊断和目前的分类复杂化，并对自然发生的朊病毒疾病的发病机制具有影响。在本研究中，我们调查了PrPSc 1型和2型共现的患病率，以及其对疾病表型和PrPSc菌株特征的影响，对比分析了34例PrP基因密码子129处全蛋氨酸纯合的sCJD （sCJDMM）。为了尽量减少对携带PrPSc 1型和2型（sCJDMM1-2）的sCJDMM病例患病率的高估，我们使用蛋白酶K浓度来水解不完全消化产生的所有片段，同时保留蛋白酶抗性PrPSc核心。此外，我们使用了几种抗体来最大限度地检测两种PrPSc类型。我们的数据显示，仅与PrPSc 1型（sCJDMM1）或PrPSc 2型（sCJDMM2）相关的sCJDMM病例确实存在；我们估计它们分别占所有sCJDMM病例的56%和5%；而在39%的病例中，PrPSc 1型和2型同时存在（sCJDMM1-2），要么混合在同一解剖区域，要么单独在不同区域。临床上，sCJDMM1-2的平均病程介于其他两种sCJDMM亚型之间。除了小脑与sCJDMM1相似外，组织病理学也处于中等水平。这些特征，连同PrP免疫染色模式，提供了诊断线索。我们还观察到疾病持续时间与PrPSc 2型和sCJDMM2表型的患病率之间的相关性。不同抗体的使用和构象稳定性免疫分析表明，1型和2型在同一解剖区域共存可能赋予1型和2型PrPSc特殊的构象特征。所有这些发现表明，sCJDMM1-2应该被视为一个独立的实体。
Five phenotypically distinct subtypes have been identified in sporadic Creutzfeldt-Jakob disease (sCJD), based on the methionine/valine polymorphic genotype of codon 129 of the prion protein (PrP) gene and the presence of either one of the two protease K-resistant scrapie prion protein (PrPSc) types identified as 1 and 2. The infrequent co-existence of both PrPSc types in the same case has been known for a long time. Recently, it has been reported, using type-specific antibodies, that the PrPSc type 1 is present in all cases of sCJD carrying PrPSc type 2. The consistent co-occurrence of both PrPSc types complicates the diagnosis and the current classification of sCJD, and has implications for the pathogenesis of naturally occurring prion diseases. In the present study, we investigated the prevalence of PrPSc types 1 and 2 co-occurrence, along with its effects on the disease phenotype and PrPSc strain characteristics, comparatively analysing 34 cases of sCJD, all methionine homozygous at codon 129 of the PrP gene (sCJDMM). To minimize overestimating the prevalence of the sCJDMM cases carrying PrPSc types 1 and 2 (sCJDMM1-2), we used proteinase K concentrations designed to hydrolyse all fragments resulting from an incomplete digestion, while preserving the protease-resistant PrPSc core. Furthermore, we used several antibodies to maximize the detection of both PrPSc types. Our data show that sCJDMM cases associated exclusively with either PrPSc type 1 (sCJDMM1) or PrPSc type 2 (sCJDMM2) do exist; we estimate that they account for approximately 56% and 5% of all the sCJDMM cases, respectively; while in 39% of the cases, both PrPSc types 1 and 2 are present together (sCJDMM1-2) either mixed in the same anatomical region or separate in different regions. Clinically, sCJDMM1-2 had an average disease duration intermediate between the other two sCJDMM subtypes. The histopathology was also intermediate, except for the cerebellum where it resembled that of sCJDMM1. These features, along with the PrP immunostaining pattern, offer a diagnostic clue. We also observed a correlation between the disease duration and the prevalence of PrPSc type 2 and sCJDMM2 phenotypes. The use of different antibodies and of the conformational stability immunoassay indicated that the co-existence of types 1 and 2 in the same anatomical region may confer special conformational characteristics to PrPSc types 1 and 2. All of these findings indicate that sCJDMM1-2 should be considered as a separate entity at this time.