The pathways to prion formation in the response to oxidative stress

氧化应激反应中朊病毒形成的途径

• 批准号: BB/S005420/1
• 负责人: Christopher Grant
• 金额: $ 52.77万
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FS005420%2F1
• 关键词: pathways; prion; formation; response; oxidative

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.

朊病毒是与以人类克雅氏病（CreutzfeldtJakobDisease，CJD）为代表的一组传染性神经退行性疾病相关的仅蛋白质的感染因子。虽然克雅氏病是一种罕见的疾病，但它与其他更常见的非传染性脑部疾病（如阿尔茨海默病）有许多共同的病理特征。尽管它具有传染性，但大多数人类克雅氏病病例是自发出现的，没有任何证据表明被相关的传染性实体朊病毒感染。然而，目前对朊病毒如何自发形成感染性结构的分子基础知之甚少。朊病毒是一种引人注目的传染性病原体，因为它们只由一种单一的蛋白质组成，而这种蛋白质是通常在大脑中发现的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导致散发性CJD的，以及是什么触发了它们的形成，知之甚少。为了帮助我们解决这些问题，我们建议研究在面包酵母（酿酒酵母）中发现的朊病毒。大约30年前，朊病毒首次在这种真菌中被描述，随后对酵母朊病毒的研究揭示了朊病毒生物学的许多迷人的新方面。在我们最近的研究中，我们发现某些被称为活性氧（或ROS）的危险形式的氧可以触发酵母中朊病毒的自发形成，因为细胞缺乏防止这种氧化损伤的防御系统，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正常可溶性蛋白质触发其转化为朊病毒的形式。重要的是，我们新的遗传学方法将有助于理解人类和动物中朊病毒形成的潜在机制。从长远来看，这些研究的结果可能揭示朊病毒疾病治疗/管理中潜在治疗干预的候选者。

项目成果

Tolerance to nascent protein misfolding stress requires fine-tuning of the cAMP/PKA pathway.

• DOI: 10.1016/j.jbc.2021.100690
• 发表时间: 2021-01
• 期刊: The Journal of biological chemistry
• 作者: Kritsiligkou P;Nowicki-Osuch K;Carter Z;Kershaw CJ;Creamer DR;Weids AJ;Grant CM
• 通讯作者: Grant CM

Sequestrase chaperones protect against oxidative stress-induced protein aggregation and [PSI+] prion formation

• DOI: 10.1371/journal.pgen.1011194
• 发表时间: 2024-02-01
• 期刊: PLOS GENETICS
• 影响因子: 4.5
• 作者: Carter，Zorana;Creamer，Declan;Grant，Chris M.
• 通讯作者: Grant，Chris M.