Tatzelt J, Prusiner S B, Welch W J
Department of Neurology, University of California, San Francisco 94143, USA.
EMBO J. 1996 Dec 2;15(23):6363-73.
The fundamental event in prion diseases involves a conformational change in one or more of the alpha-helices of the cellular prion protein (PrP(C)) as they are converted into beta-sheets during the formation of the pathogenic isoform (PrP(Sc)). Here, we show that exposure of scrapie-infected mouse neuroblastoma (ScN2a) cells to reagents known to stabilize proteins in their native conformation reduced the rate and extent of PrP(Sc) formation. Such reagents include the cellular osmolytes glycerol and trimethylamine N-oxide (TMAO) and the organic solvent dimethylsulfoxide (DMSO), which we refer to as 'chemical chaperones' because of their influence on protein folding. Although the chemical chaperones did not appear to affect the existing population of PrP(Sc) molecules in ScN2a cells, they did interfere with the formation of PrP(Sc) from newly synthesized PrP(C). We suggest that the chemical chaperones act to stabilize the alpha-helical conformation of PrP(C) and thereby prevent the protein from undergoing a conformational change to produce PrP(Sc). These observations provide further support for the idea that prions arise due to a change in protein conformation and reveal potential strategies for preventing PrP(Sc) formation.
朊病毒疾病的基本事件涉及细胞朊病毒蛋白（PrP(C)）的一个或多个α螺旋在转变为致病性异构体（PrP(Sc)）的过程中转化为β折叠时发生的构象变化。在此，我们表明，将感染羊瘙痒病的小鼠神经母细胞瘤（ScN2a）细胞暴露于已知能稳定蛋白质天然构象的试剂中，可降低PrP(Sc)形成的速率和程度。这类试剂包括细胞渗透剂甘油和三甲胺N-氧化物（TMAO）以及有机溶剂二甲基亚砜（DMSO），由于它们对蛋白质折叠有影响，我们将其称为“化学伴侣”。尽管化学伴侣似乎并未影响ScN2a细胞中现有PrP(Sc)分子群体，但它们确实干扰了新合成的PrP(C)形成PrP(Sc)的过程。我们认为化学伴侣的作用是稳定PrP(C)的α螺旋构象，从而防止该蛋白发生构象变化以产生PrP(Sc)。这些观察结果为朊病毒因蛋白质构象变化而产生这一观点提供了进一步支持，并揭示了预防PrP(Sc)形成的潜在策略。
