Gabizon R, Telling G, Meiner Z, Halimi M, Kahana I, Prusiner S B
Department of Neurology, Hadassah University Hospital, Ein Karem, Jerusalem, Israel.
Nat Med. 1996 Jan;2(1):59-64. doi: 10.1038/nm0196-59.
We studied prion proteins (PrP) in skin and brains of Libyan Jews carrying the E200K mutation who died of familial Creutzfeldt-Jakob disease (CJD). Unexpectedly, studies with brain showed that PrP molecules encoded both by the wild-type (wt) and mutant alleles exhibit altered properties characteristic of the prion protein associated with prion diseases (PrPSc). Using monospecific antisera, we found that wtPrP was insoluble in the brains of three patients who were heterozygous for the E200K mutation, whereas mutant PrP was both insoluble and protease-resistant. Our results argue that both wild-type and mutant PrP undergo conformational changes and are particularly intriguing, because the normal isoform PrPc is soluble in nondenaturing detergents and is readily digested by proteases, whereas PrPSc is insoluble and resistant to proteolytic digestion. Our findings indicate that insoluble wtPrP represents a conformational intermediate, the first to be identified, within a pathway in which PrPc is converted to PrPSc.
我们研究了携带E200K突变且死于家族性克雅氏病（CJD）的利比亚犹太人皮肤和大脑中的朊病毒蛋白（PrP）。出乎意料的是，对大脑的研究表明，野生型（wt）和突变等位基因编码的PrP分子均表现出与朊病毒疾病相关的朊病毒蛋白（PrPSc）的改变特性。使用单特异性抗血清，我们发现，在E200K突变杂合的三名患者大脑中，wtPrP不溶，而突变型PrP既不溶又具有蛋白酶抗性。我们的结果表明，野生型和突变型PrP均发生构象变化，这尤其令人感兴趣，因为正常异构体PrPc可溶于非变性去污剂并易于被蛋白酶消化，而PrPSc不溶且对蛋白水解消化具有抗性。我们的研究结果表明，不溶性wtPrP代表了PrPc转化为PrPSc途径中的一种构象中间体，这是首次被鉴定出来的。
