Induction of yeast prions by reactive oxygen species

活性氧诱导酵母朊病毒

• 批准号: BB/J000183/1
• 负责人: Christopher Grant
• 金额: $ 41.78万
• 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: 2012
• 资助国家: 英国
• 起止时间: 2012 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FJ000183%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(CJD)是一种罕见的人脑传染病，会导致痴呆症和死亡。关于这种疾病和相关疾病，如羊瘙痒病和牛海绵状脑病(疯牛病，疯牛病)，最令人费解的事实是，它们似乎是由一种独特的被称为普里恩(仅限蛋白质的传染病)的传染病引发的。虽然CJD在人类中是一种相对罕见的疾病(每年大约每一百万人中就有一人感染这种疾病)，但患者表现出许多患有其他更常见的非传染性脑部疾病的病理特征，如阿尔茨海默病和帕金森病。尽管人类CJD具有传染性，但大多数(约80%)人类CJD病例都是“零星”发生的，即自发出现，没有任何证据表明患者从第三方感染了传染性普恩病毒，或通过个人基因的突变而发生。Prion是一种引人注目的感染性病原体，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一种结构改变的蛋白质(称为PrP)。然而，我们对Prion如何自发形成导致零星的CJD，或者是什么会触发它们的形成，知之甚少。为了帮助我们解决这些问题，我们提议研究在面包酵母(酿酒酵母)中发现的普鲁恩。Prion在15年前首次在这种真菌中被描述，随后对酵母Prion的许多研究揭示了Pron生物学中迷人的、经常令人惊讶的新方面，尤其是它们的存在可能对它们感染的宿主有利而不是有害。我们建议使用两种不同的酵母蛋白--称为[PSI+]和[PIN+]--来确定是什么触发了细胞中蛋白的自发形成。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，即被称为活性氧物种(或简称ROS)的氧，可以在酵母中触发[PSI+]Prion的自发形成。在缺乏防止这种氧化损伤的防御系统的酵母细胞中，[PSI+]蛋白以非常高的频率自发形成。因为我们已经知道ROS也可以触发导致CJD的人类Pron的形成，所以我们相信通过使用现代遗传学和生物化学的方法，我们将能够确定氧化损伤在触发Prion形成中的重要性。这项研究还将扩大到包括其他人类疾病相关蛋白，这些蛋白的错误折叠也会导致大脑退化。

项目成果

Autophagy protects against de novo formation of the [PSI+] prion in yeast.

• DOI: 10.1091/mbc.e15-08-0548
• 发表时间: 2015-12-15
• 期刊: Molecular biology of the cell
• 影响因子: 3.3
• 作者: Speldewinde SH;Doronina VA;Grant CM
• 通讯作者: Grant CM

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

Sup35 methionine oxidation is a trigger for de novo [PSI(+)] prion formation.

• DOI: 10.1080/19336896.2015.1065372
• 发表时间: 2015
• 期刊: Prion
• 影响因子: 2.3
• 作者: Grant CM

[PSI(+)] turns 50.

[PSI( )] 已满 50 岁。

• DOI: 10.1080/19336896.2015.1111508
• 发表时间: 2015
• 期刊: Prion
• 影响因子: 2.3
• 作者: Tuite MF