Prion-mediated protein aggregation/co-aggregation and cellular consequence

朊病毒介导的蛋白质聚集/共聚集和细胞后果

• 批准号: 9980942
• 负责人: Zhiqiang Du
• 金额: $ 31.73万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9980942
• 关键词: Alzheimer' s Disease; Amyloid; Animals; Bacteria; Biological Process; Biology; Biotin; Carbon; Cell physiology; Cells; Chromatin Remodeling Factor; Collection; Disease; Elements; Epigenetic Process; Etiology; Event; Genetic Transcription; Human; In Vitro; Isomerism; Knowledge; Label; Laboratories; Light; Link; Mass Spectrum Analysis; Mediating; Modeling; Molecular; Molecular Conformation; Morphology; Neurodegenerative Disorders; Organism; Pathogenicity; Pathology; Phenotype; Physiological; Plants; Play; PrP; PrPSc Proteins; Prion Diseases; Prions; Proteins; Research; Role; Saccharomyces cerevisiae; Saccharomycetales; Source; Stress; Structure; Study models; Subgroup; Switching Complex; Testing; Tissues; Transcriptional Regulation; Yeasts; amyloid formation; amyloid structure; amyloidogenesis; base; cell behavior; cell growth regulation; conformer; dimorphism; fungus; insight; link protein; neurotoxicity; novel therapeutics; pathogen; prion-based; prion-like; protein aggregation; protein misfolding; response; success; trait; transmission process; yeast prion

Prion diseases, also known as transmissible spongiform encephalopathies (TSEs), belong to a subgroup of mammalian protein-misfolding neurodegenerative disorders. The pathogens responsible for TSEs are a collection of misfolded conformers (PrPSc) of an otherwise normal cellular protein (PrPC). The mechanism underlying such a conformational switch is yet ambiguous, and TSEs currently remain devastating and incurable. Intriguingly, prion or prion-like proteins have been identified in a broad range of eukaryotic and prokaryotic organisms, playing important roles in not only disease pathologies but also normal biological functions. These aggregation-prone proteins are common in forming self-sustaining conformations (usually amyloids) that can be transmitted from cell to cell, or tissue to tissue. However, we are still in an early stage in elucidating the amyloid-mediated mechanisms that contribute to diverse cellular phenotypes and pathologies. In the budding yeast Saccharomyces cerevisiae, at least eight prion proteins have been verified, which have been proven valuable models for studying prion biology. For example, the Swi1 prion ([SWI+]) discovered in our laboratory is normally a subunit of the ATP-dependent chromatin-remodeling complex SWI/SNF, and is the first prion shown to involve in massive transcriptional regulation of yeast. Upon the conformational switch, cells carrying the [SWI+] prion show a compromised capacity in using non-glucose carbon sources and a complete loss of multicellular features. However, the structural determinants of [SWI+] and their roles in prion-mediated cellular behaviors are still elusive. Moreover, accumulated evidence suggests that distinct yeast prions may interact and act in concert to regulate important cellular traits such as yeast dimorphism – switching between a unicellular form and multicellular forms, involving abundant protein interaction events such as co-aggregation. Thus, in this project, we propose to characterize the sequence features (residues) of Swi1 that are essential for Swi1 amyloid formation, [SWI+] formation and propagation. We also plan to investigate how the Swi1 prion interacts with other prions, such as Mot3 ([MOT3+]) and/or Cyc8 ([OCT+]) prions to regulate yeast multicellularity and global gene transcription in response to cellular and environmental conditions. Finally, we plan to identify prion-interacting proteins and cellular machineries, and examine the significance of such interactions in amyloidogenesis and prion transmission. The success of this project will shed light on the structure of amyloid-forming proteins, and the mechanism governing protein amyloidogenesis, prion transmission, and protein interactions, which are tightly linked to prion- mediated cellular phenotypes and human protein misfolding diseases such as Alzheimer's diseases (AD).

朊病毒病，也称为传染性海绵状脑病（TSE）， 属于哺乳动物蛋白质错误折叠神经退行性疾病的一个亚组。这 导致 TSE 的病原体是错误折叠构象异构体 (PrPSc) 的集合 否则为正常细胞蛋白（PrPC）。这种构象背后的机制 转变尚不明确，TSE 目前仍然具有破坏性且无法治愈。有趣的是， 朊病毒或朊病毒样蛋白已在广泛的真核和原核生物中被鉴定 生物体，不仅在疾病病理学中发挥着重要作用，而且在正常生物学中也发挥着重要作用 功能。这些易于聚集的蛋白质在形成自我维持方面很常见 可以在细胞之间或组织之间传播的构象（通常是淀粉样蛋白）。 然而，我们仍处于阐明淀粉样蛋白介导机制的早期阶段 有助于不同的细胞表型和病理学。在芽殖酵母中 酿酒酵母中，至少有八种朊病毒蛋白已被验证，它们已被证明是有价值的 研究朊病毒生物学的模型。例如，在我们的研究中发现的 Swi1 朊病毒 ([SWI+]) 实验室通常是 ATP 依赖性染色质重塑复合物 SWI/SNF 的一个亚基， 它是第一个被证明参与酵母大规模转录调控的朊病毒。于 构象转换，携带[SWI+]朊病毒的细胞显示出使用能力受损 非葡萄糖碳源和多细胞特征完全丧失。然而， [SWI+] 的结构决定因素及其在朊病毒介导的细胞行为中的作用仍不清楚 难以捉摸。此外，积累的证据表明，不同的酵母朊病毒可能相互作用并 协同作用来调节重要的细胞特征，例如酵母二态性——之间的切换 单细胞形式和多细胞形式，涉及丰富的蛋白质相互作用事件，例如 共聚合。因此，在这个项目中，我们建议表征序列特征 Swi1 的（残基）对于 Swi1 淀粉样蛋白的形成、[SWI+] 的形成和 传播。我们还计划研究 Swi1 朊病毒如何与其他朊病毒相互作用，例如 Mot3 ([MOT3+]) 和/或 Cyc8 ([OCT+]) 朊病毒调节酵母多细胞性和全局基因 转录响应细胞和环境条件。最后，我们计划确定 朊病毒相互作用蛋白和细胞机器，并检查此类的重要性 淀粉样蛋白生成和朊病毒传播中的相互作用。该项目的成功将流 阐明淀粉样蛋白形成蛋白的结构以及控制蛋白的机制 淀粉样蛋白形成、朊病毒传播和蛋白质相互作用，这些都与朊病毒密切相关 介导的细胞表型和人类蛋白质错误折叠疾病，例如阿尔茨海默病 疾病（AD）。