Endogenous proteolytic cleavage of normal and disease-associated isoforms of the human prion protein in neural and non-neural tissues
Endogenous proteolytic cleavage of normal and disease-associated isoforms of the human prion protein in neural and non-neural tissues
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DOI：
10.1016/s0002-9440(10)65744-6
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发表时间：
1998-11-01
影响因子：
6
通讯作者：
Prelli, F
中科院分区：
文献类型：
--
作者：
Jiménez-Huete, A;Lievens, PMJ;Prelli, F
我们已经调查了蛋白水解裂解的细胞（PrPC）和病理（PrPSc）亚型的人朊病毒蛋白（PrP）在正常和朊病毒影响的大脑和扁桃体和血小板从神经系统完整的个人。去糖基化后，根据其电泳迁移率、免疫反应性、肌氨酸溶解度以及对内源性蛋白酶的抗性（作为一种新方法），分离了各种PrP物质。首先，我们的数据表明，大脑中的PrPC蛋白水解源自21至22和18（C1）kd的氨基截短肽，它们在不同区域相似，并且没有被PrP密码子129基因型修饰，一种影响朊病毒疾病表达的多态性。第二，PrPC在脑中的这种蛋白水解裂解被金属蛋白酶的抑制剂阻断。第三，差异PrPC蛋白水解，并可能在天冬酰胺糖基化和糖基磷脂酰肌醇锚组成，存在于神经和非神经组织之间。第四，散发性克雅氏病（CJD）和Gerstmann-Straussler-Scheinker F198 S病脑中的蛋白酶抗性PrPSc核心都具有完整的C1切割位点（Met 111-His 112），这排除了与毒性和纤维形成相关的结构域的破坏。第五，内源性蛋白水解PrPSc肽的分布是所研究的每种疾病的特征，因此允许在不使用蛋白酶K的情况下对这些朊病毒疾病进行分子分类，甚至允许识别具有不同密码子129基因型和神经病理表型的2型CJD患者中的PrPSc异质性，这并不排除表型表达中其他因子的作用;特别是糖基化的差异，这可能与新的变异型克雅氏病特别相关。PrP的蛋白水解加工可能在朊病毒疾病的嗜神经性和表型表达中起重要作用，但似乎不参与疾病易感性。
We have investigated the proteolytic cleavage of the cellular (PrPC) and pathological (PrPSc) isoforms of the human prion protein (PrP) in normal and prion-affected brains and in tonsils and platelets from neurologically intact individuals. The various PrP species were resolved after deglycosylation according to their electrophoretic mobility, immunoreactivity, Sarkosyl solubility, and, as a novel approach, resistance to endogenous proteases, First, our data show that PrPC proteolysis in brain originates amino-truncated peptides of 21 to 22 and 18 (C1) kd that are similar in different regions and are not modified by the PrP codon 129 genotype, a polymorphism that affects the expression of prion disorders. Second, this proteolytic cleavage of PrPC in brain is blocked by inhibitors of metalloproteases. Third, differences in PrPC proteolysis, and probably in Asn glycosylation and glycosylphosphatidylinositol anchor composition, exist between neural and non-neural tissues. Fourth, protease-resistant PrPSc cores in sporadic Creutzfeldt-Jakob disease (CJD) and Gerstmann-Straussler-Scheinker F198S disease brains all have an intact C1 cleavage site (Met111-His112), which precludes disruption of a domain associated with toxicity and fibrillogenesis. Fifth, the profile of endogenous proteolytic PrPSc peptides is characteristic of each disorder studied, thus permitting the molecular classification of these prion diseases without the use of proteinase K and even a recognition of PrPSc heterogeneity within type 2 CJD patients having different codon 129 genotype and neuropathological phenotype, This does not exclude the role of additional factors in phenotypic expression; in particular, differences in glycosylation that may be especially relevant in the new variant CJD. Proteolytic processing of PrP may play an important role in the neurotropism and phenotypic expression of prion diseases, but it does not appear to participate in disease susceptibility.