Effect of the E200K mutation on prion protein metabolism - Comparative study of a cell model and human brain
Effect of the E200K mutation on prion protein metabolism - Comparative study of a cell model and human brain
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DOI：
10.1016/s0002-9440(10)64572-5
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发表时间：
2000-08-01
影响因子：
6
通讯作者：
Petersen, RB
中科院分区：
文献类型：
--
作者：
Capellari, S;Parchi, P;Petersen, RB
朊病毒疾病的标志是正常细胞蛋白，朊病毒蛋白（PrPC）的构象改变异构体（PrPSc）在大脑中的积累。在遗传形式中，朊蛋白基因的突变被认为是通过改变突变PrP （PrPM）的代谢从而导致其转化为PrPSc而引起疾病的。我们利用细胞模型研究了携带谷氨酸到赖氨酸在残基200 （E200K）的PrPM的生物合成和加工，这与最常见的遗传性人类朊病毒疾病有关。PrPM在197个残基上含有一个异常的聚糖，产生了更多的截断片段。此外，PrPM显示未糖基化异构体到细胞表面的运输受损。在克雅氏病E200K变异患者的大脑中分离的PrP中也发现了类似的变化。虽然细胞PrPM表现出PrPSc的一些特征，但在E200K脑中发现的PrPSc在数量和质量上存在差异。我们认为E200K突变在细胞模型和大脑中引起相同的PrPM代谢变化。然而，在大脑中，PrPM通过年龄依赖机制经历额外的修饰，导致PrPSc的形成和疾病的发展。
The hallmark of prion diseases is the cerebral accumulation of a conformationally altered isoform (PrPSc) of a normal cellular protein, the prion protein (PrPC). In the inherited form, mutations in the prion protein gene are thought to cause the disease by altering the metabolism of the mutant PrP (PrPM) engendering its conversion into PrPSc. We used a cell model to study biosynthesis and processing of PrPM carrying the glutamic acid to lysine substitution at residue 200 (E200K), which Is linked to the most common inherited human prion disease. PrPM contained an aberrant glycan at residue 197 and generated an increased quantity of truncated fragments. In addition, PrPM showed impaired transport of the unglycosylated isoform to the cell surface. Similar changes were found in the PrP isolated from brains of patients affected by the E200K variant of Creutzfeldt-Jakob disease. Although the cellular PrPM displayed some characteristics of PrPSc, the PrPSc found in the E200K brains was quantitatively and qualitatively different. We propose that the E200K mutation cause the same metabolic changes of PrPM in the cell model and in the brain. However, in the brain, PrPM undergoes additional modifications, by an age-dependent mechanism that leads to the formation of PrPSc and the development of the disease.