Induction of yeast prions by reactive oxygen species

活性氧诱导酵母朊病毒

• 批准号: BB/J000191/1
• 负责人: Mick Tuite
• 金额: $ 41.91万
• 依托单位: University of Kent
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2011
• 资助国家: 英国
• 起止时间: 2011 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FJ000191%2F1
• 关键词: Induction; yeast; prions; reactive; oxygen

Creutzfeldt-Jakob Disease (CJD) is an unusual infectious disease of the human brain that leads to dementia and death. The most baffling fact about this and related diseases such as sheep scrapie and bovine spongiform encephalopathy (BSE, Mad Cow Disease) is that they appear to be triggered by a unique class of infectious agent known as a prion (protein-only infectious agent). Although CJD is a comparatively rare disease in humans (approximately 1 in a million people will contract the disease in any one year), sufferers show many of the pathological features seen in individuals suffering from other more common, non-infectious diseases of the brain such as Alzheimer's Disease and Parkinson's Disease. In spite of its infectious nature, the majority of cases of human CJD (~80%) are known to occur 'sporadically' i.e. appear spontaneously, without any evidence of the diseased individual acquiring an infectious prion from a third party, or through a mutation in the individual's genes. Prions are remarkable infectious agents because they consist only of a single protein that is a structurally altered form of a protein (called PrP) normally found in the brain. Yet we know remarkably 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 over 15 years ago and the many subsequent studies on yeast prions have revealed fascinating often surprising new aspects of prion biology not least the fact that their presence can be of benefit to the host they infect rather than detrimental. We are proposing to use two different yeast prions - called [PSI+] and [PIN+] - to identify what triggers the spontaneous formation of a prion in the cell. The approach we are taking is based on our recent discovery that certain potentially dangerous forms of oxygen known as 'reactive oxygen species' (or ROS for short) can trigger the spontaneous formation of the [PSI+] prion in yeast. In yeast cells lacking a defence system known to prevent such oxidative damage, the [PSI+] prion formed spontaneously at a remarkably high frequency. Because it is already known that ROS can also trigger the formation of the human prion that causes CJD then we believe that by using modern methods of genetics and biochemistry, we will be able to establish the significance of oxidative damage in triggering prion formation. This study will also be extended to include other human disease associated proteins whose misfolding also leads to brain degeneration.

克雅氏病（Creutzfeldt-Jakob Disease，CJD）是一种罕见的人类大脑传染病，可导致痴呆和死亡。最令人困惑的事实是，这种疾病和相关疾病，如羊瘙痒症和牛海绵状脑病（疯牛病），它们似乎是由一类独特的感染因子引起的，这种感染因子被称为朊病毒（蛋白质感染因子）。虽然克雅氏病在人类中是一种相对罕见的疾病（每年约有百万分之一的人会感染这种疾病），但患者表现出许多在患有其他更常见的非传染性脑部疾病（如阿尔茨海默病和帕金森病）的个体中看到的病理特征。尽管具有传染性，但已知大多数人类克雅氏病病例（约80%）是“偶发性”发生的，即自发出现，没有任何证据表明患病个体从第三方获得传染性朊病毒，或通过个体基因突变。朊病毒是一种引人注目的传染因子，因为它们只由一种蛋白质组成，这种蛋白质是通常在大脑中发现的蛋白质（称为PrP）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。朊病毒在15年前首次在这种真菌中被描述，随后对酵母朊病毒的许多研究揭示了朊病毒生物学的迷人的、往往令人惊讶的新方面，尤其是它们的存在对它们感染的宿主有益而不是有害。我们建议使用两种不同的酵母朊病毒-称为[PSI+]和[PIN+] -来确定是什么触发了细胞中朊病毒的自发形成。我们正在采取的方法是基于我们最近的发现，即某些潜在危险的氧形式，称为“活性氧”（简称ROS），可以触发酵母中[PSI+]朊病毒的自发形成。在酵母细胞中，由于缺乏已知的防御系统来防止这种氧化损伤，[PSI+]朊病毒以非常高的频率自发形成。因为我们已经知道活性氧也可以触发导致克雅氏病的人类朊病毒的形成，所以我们相信通过使用现代遗传学和生物化学方法，我们将能够确定氧化损伤在触发朊病毒形成中的重要性。这项研究还将扩展到包括其他人类疾病相关的蛋白质，这些蛋白质的错误折叠也会导致大脑退化。

项目成果

B07 Aggregation-prone Proteins Exacerbate Huntingtin Toxicity In Yeast And Drosophila

B07 易聚集蛋白会加剧酵母和果蝇中亨廷顿蛋白的毒性

• DOI: 10.1136/jnnp-2014-309032.35
• 发表时间: 2014
• 期刊: Journal of Neurology, Neurosurgery & Psychiatry
• 作者: Branco Dos Santos J

The life of [PSI].

[psi]的生活。

• DOI: 10.1007/s00294-017-0714-7
• 发表时间: 2018-03
• 期刊: Current genetics
• 影响因子: 2.5
• 作者: Cox B;Tuite M
• 通讯作者: Tuite M

Disrupting the cortical actin cytoskeleton points to two distinct mechanisms of yeast [PSI+] prion formation.

• DOI: 10.1371/journal.pgen.1006708
• 发表时间: 2017-04
• 期刊: PLoS genetics
• 影响因子: 4.5
• 作者: Speldewinde SH;Doronina VA;Tuite MF;Grant CM
• 通讯作者: Grant CM

Oxidative stress conditions increase the frequency of de novo formation of the yeast [PSI+] prion.

• DOI: 10.1111/mmi.12930
• 发表时间: 2015-04
• 期刊: Molecular microbiology
• 影响因子: 3.6
• 作者: Doronina VA;Staniforth GL;Speldewinde SH;Tuite MF;Grant CM
• 通讯作者: Grant CM

New links between SOD1 and metabolic dysfunction from a yeast model of amyotrophic lateral sclerosis.

• DOI: 10.1242/jcs.190298
• 发表时间: 2016-11-01
• 期刊: Journal of cell science
• 影响因子: 4
• 作者: Bastow EL;Peswani AR;Tarrant DS;Pentland DR;Chen X;Morgan A;Staniforth GL;Tullet JM;Rowe ML;Howard MJ;Tuite MF;Gourlay CW
• 通讯作者: Gourlay CW