The pathways to prion formation in the response to oxidative stress

朊病毒是与以人类克雅氏病（CJD）为典型的一组传染性神经退行性疾病相关的蛋白感染因子。虽然CJD是一种罕见的疾病，但它与其他更常见的非传染性大脑疾病（如阿尔茨海默病）有许多共同的病理特征。尽管人类克雅氏病具有传染性，但大多数病例是自发出现的，没有任何证据表明感染了相关的感染性实体，即朊病毒。然而，目前对朊病毒如何自发形成感染性结构的分子基础了解甚少。朊病毒是一种显著的传染性病原体，因为它们只由一种蛋白质组成，这种蛋白质是大脑中通常发现的一种蛋白质的结构改变形式。然而，我们对朊病毒是如何自发形成并引起散发性克雅氏病的知之甚少，也不知道是什么触发了它们的形成。为了帮助我们解决这些问题，我们建议研究在贝克酵母（酿酒酵母）中发现的朊病毒。大约30年前，在这种真菌中首次发现了朊病毒，随后对酵母朊病毒的研究揭示了朊病毒生物学的许多有趣的新方面。在我们最近的研究中，我们发现某些危险形式的氧被称为活性氧（ROS）可以触发酵母中朊病毒的自发形成，因为细胞缺乏防御系统来防止这种氧化损伤，以非常高的频率自发形成朊病毒。我们现在感兴趣的是确定氧化损伤如何触发正常可溶性蛋白转化为朊病毒形式。重要的是，我们的新遗传方法将有助于理解人类和动物中朊病毒形成的潜在机制。因此，从长远来看，这些研究的结果可能会揭示在朊病毒疾病的治疗/管理中潜在治疗干预的候选药物。

Prions are protein-only infectious agents associated with a group of transmissible neurodegenerative diseases typified by human Creutzfeldt Jakob Disease (CJD). Although CJD is a rare disease, it shares many pathological features with other more common, non-infectious diseases of the brain such as Alzheimer's disease. In spite of its infectious nature, the majority of cases of human CJD appear spontaneously, without any evidence of infection by the associated infectious entity, the prion. However, the molecular basis of how prions form spontaneously into infectious structures is poorly understood at present. Prions are remarkable infectious agents because they consist only of a single protein that is a structurally altered form of a protein normally found in the brain. Yet we know very little about how prions form spontaneously to cause sporadic CJD or for that matter what will trigger their formation. To help us address these questions we are proposing to study prions that are found in Baker's yeast (Saccharomyces cerevisiae). Prions were first described in this fungus some 30 years ago and the subsequent studies on yeast prions have revealed many fascinating new aspects of prion biology. In our recent research we have discovered that certain dangerous forms of oxygen known as reactive oxygen species (or ROS) can trigger the spontaneous formation of prions in yeast, because cells lacking the defence system preventing such oxidative damage, form prions spontaneously at a remarkably high frequency. We are now interested in determining how oxidative damage to a normally soluble protein triggers its conversion into the prion form. Importantly, our novel genetic approaches will be relevant to understanding the underlying mechanisms of prion formation in man and animals. In the long term, findings from these studies may therefore reveal candidates for potential therapeutic intervention in the treatment/management of prion diseases.