Allelic origin of the abnormal prion protein isoform in familial prion diseases
Allelic origin of the abnormal prion protein isoform in familial prion diseases
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DOI：
10.1038/nm0997-1009
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发表时间：
1997-09-01
期刊：
影响因子：
82.9
通讯作者：
Gambetti, P
中科院分区：
文献类型：
--
作者：
Chen, SG;Parchi, P;Gambetti, P
朊病毒疾病的标志是朊病毒蛋白（PrPres）的异常同种型的存在，其不溶于非变性去污剂并且对蛋白酶具有抗性。我们研究了与致死性家族性失眠症（FFI）和克雅氏病（CJD（178））亚型相关的D178N突变杂合子以及与另一种CJD亚型相关的插入突变杂合子受试者大脑中PrPres的等位基因起源。我们发现，在FFI和CJD（178）受试者中，只有突变型PrP是不溶于洗涤剂和耐蛋白酶的。因此，PrPres仅来源于携带D178N突变的突变等位基因。相反，在携带插入突变的CJD亚型中，野生型PrP也是洗涤剂不溶性的，并且可能是蛋白酶抗性的。我们的研究结果表明，参与野生型PrP在PrPres的形成取决于突变的类型，提供了一个深入了解的分子机制，在家族性朊病毒疾病的表型异质性。
The hallmark of prion diseases is the presence of an aberrant isoform of the prion protein (PrPres) that is insoluble in nondenaturing detergents and resistant to proteases. We investigated the allelic origin of PrPres in brains of subjects heterozygous for the D178N mutation linked to fatal familial insomnia (FFI) and a subtype of Creutzfeldt-Jakob disease (CJD(178)), as well as for insertional mutations associated with another CJD subtype. We found that in FFI and CJD(178) subjects, only mutant PrP was detergent-insoluble and protease-resistant. Therefore, PrPres derives exclusively from the mutant allele carrying the D178N mutation. In contrast, in the CJD subtype harboring insertional mutations, wild-type PrP was also detergent-insoluble and likely to be protease-resistant. Our findings indicate that the participation of the wild-type PrP in the formation of PrPres depends on the type of mutations, providing an insight into the molecular mechanisms underlying the phenotypic heterogeneity in familial prion diseases.