Analysis of the influence of residue 219 polymorphism of prion protein on human prion diseases

朊病毒蛋白219残基多态性对人类朊病毒疾病的影响分析

基本信息

批准号：
13670203
负责人：
MURAMOTO Tamaki
金额：
$ 2.5万
依托单位：
Tohoku University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2002
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13670203/
关键词：
Creutzfeldt-Jakob disease prion protein polymorphism dura mater grafting abnormal isoform subtype

项目摘要

We investigated cases of dura grafl-associated Creutzfeldt-Jakob disease(CJD) and discovered that there are at least two subtypes of this entity that differ in clinical, pathological and biochemical characteristics. The clinical difference included the absence or relatively late appearance of myoclonus and characteristic eledroencephalographic changes, and slow transition into akinetic mutism in the subtype with prion protein plaques in comparison with that without plaques. The pathological difference included relatively milder brain atrophy and various unique morphologies of PrP depositions in the subtype with plaques. The biochemical difference was represented by a novel 11-12 kDa protease-resistant prion protein (PrP) fragment in brain tissue that is detected in the subtype without plaques but not in that with plaques. As for PrP gene, the subtypes were homogenous on polymorphism with the codons 129 Met/Met and 219 Glu/Glu homozygosity and without mutations.To explore the association of the 11-12 kDa PrP fragment with other prion diseases, we investigated cases of sporadic, genetic and variant CJD and discovered that the PrP fragment is associaied with particular types or subtypes of these entities and is not found in unaffected subjects. It was detected not only in protease-resistant protein fractions but also untreated total lysate fractions from the affected brain tissues, and was as insoluble as the authentic abnormal isoform of PrP (PrPSc). These findings strongly argue that the PrP fragment is closely related to the pathogenesis of prion diseases. The patients were homozygous for the codon 219 Glu polymorphism.Through all these studies, disease types with PrP plaques were unassociated with the PrP fragment, implicating shared mechanisms in their origins.In these analyses, we also discovered that CJD associated with the codon 232 substitution of Argfor Met features in the deposition of the type 1 PrPSc in brain tissue.

我们调查了与硬脑膜相关的克雅氏病（CJD）病例，发现该实体至少有两种在临床、病理和生化特征上不同的亚型。临床差异包括，与无斑块的亚型相比，有朊病毒蛋白斑块的亚型不存在或相对较晚出现肌阵挛和特征性脑电图改变，以及缓慢转变为运动不能性沉默症。病理学差异包括相对较轻的脑萎缩和斑块亚型中各种独特的PrP沉积形态。生化差异表现为脑组织中新的 11-12 kDa 蛋白酶抗性朊病毒蛋白 (PrP) 片段，该片段在无斑块的亚型中检测到，但在有斑块的亚型中未检测到。至于PrP基因，其亚型在多态性上是同质的，密码子129 Met/Met和219 Glu/Glu纯合性并且没有突变。为了探讨11-12 kDa PrP片段与其他朊病毒疾病的关联，我们调查了散发性的病例。、遗传性和变异型克雅氏病，并发现 PrP 片段与这些实体的特定类型或亚型相关，并且在不受影响的科目。它不仅在蛋白酶抗性蛋白组分中检测到，而且在受影响脑组织的未经处理的总裂解物组分中也检测到，并且与真正的 PrP 异常异构体 (PrPSc) 一样不溶。这些发现有力地证明了 PrP 片段与朊病毒疾病的发病机制密切相关。这些患者的密码子 219 Glu 多态性是纯合的。通过所有这些研究，具有 PrP 斑块的疾病类型与 PrP 片段无关，这表明它们的起源具有共同的机制。在这些分析中，我们还发现克雅氏病与密码子 232 替换相关Argfor Met 在脑组织中 1 型 PrPSc 沉积中的作用。