Genetic Study of the Yeast Prion-Interacting Proteins

酵母朊病毒相互作用蛋白的遗传学研究

• 批准号: 7545445
• 负责人: YURY O CHERNOFF
• 金额: $ 26.79万
• 依托单位: GEORGIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-01-01 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7545445
• 关键词: Actins; Address; Alzheimer' s Disease; Amyloid; Amyloid Proteins; Amyloidosis; Autophagocytosis; Bovine Spongiform Encephalopathy; Budgets; Cell division; Cells; Complex; Cytoskeletal Proteins; Cytoskeleton; Data; Disease; Endocytic Vesicle; Endocytosis; Equilibrium; Family; Generations; Genetic; Golgi Apparatus; Growth; Health; Human; Huntington Disease; Inclusion Bodies; Individual; Longevity; Mammals; Meat; Mediating; Micromanipulation; Modeling; Molecular Chaperones; Monitor; Neurodegenerative Disorders; Parkinson Disease; Pathway interactions; Pattern; Polymers; Population; Prion Diseases; Prions; Process; Proliferating; Protein Isoforms; Proteins; Public Health; Research; Research Personnel; Role; Solutions; Structure; System; Testing; Vacuole; Work; Yeasts; age related; base; chronic wasting disease of elk and deer; cytotoxicity; design; model development; multicatalytic endopeptidase complex; non-prion; polyglutamine; prion-based; programs; protein aggregate; research study; trafficking; trait; transmission process; yeast prion

Prions are self-perpetuating protein isoforms that cause fatal neurodegenerative diseases in mammals and humans and control heritable traits in yeast. Most prions known to date form highly ordered fibrous polymers (amyloids), resembling aggregates involved in non-transmissible amyloidoses, such as Alzheimer's and Parkinson's diseases, or in polyglutamine disorders such as Huntington's disease. Mechanisms of clearance of the amyloid proteins are poorly understood. It is shown by us and other groups that prion propagation in yeast occurs via subsequent cycles of polymer fragmentation and growth, mediated by chaperone proteins. Accumulation of the large cytologically detectable aggregated structures (inclusion bodies) of prion proteins or other amyloidogenic proteins is observed in yeast in certain conditions and is sometimes associated with cytotoxicity. It is demonstrated by our data that some inclusion bodies interact with actin cytoskeletal networks, involved in endocytosis and trafficking of the endocytic vesicles to the vacuole. It is proposed that: 1) inclusion bodies represent intermediates in the prion generation or prion elimination pathways, and 2) prion propagation is regulated by a dynamic equilibrium between the actively proliferating prion units and inclusion bodies incapable of efficient propagation. Chaperones, proteolytic systems, cytoskeletal networks and trafficking pathways modulate prion propagation and clearance by shifting the equilibrium between inclusion bodies and proliferating prion units. Our proposal for the next budget period is designed to test specific predictions based on this general model. Specific aims of the project will specifically address the roles of chaperones, proteolytic pathways, cytoskeletal networks and intracellular trafficking pathways in generation and clearance of the prion protein aggregates. Taken together, the results of these experiments will uncover the mechanism of clearance of aggregated amyloidogenic proteins in yeast cells Relevance to public health: Mammalian prion diseases and many other amyloidoses are fatal and incurable. Mammalian prion diseases, such as "mad cow" disease and chronic wasting disease of elk and deer, represent a significant health threat due to a possibility of their transmission to humans with infected meat. Some amyloid diseases, such as Alzheimer's disease, are widespread and age-dependent, so that their importance is going to grow further in parallel with the eradication of other diseases and improvement of the average life span of human populations. This research will further establish yeast as a model for development of the strategies counteracting accumulation and propagation of prions and other toxic amyloids.

朊病毒是一种自我延续的蛋白质异构体，可导致哺乳动物致命的神经退行性疾病 和人类并控制酵母的遗传性状。迄今为止已知的大多数朊病毒形成高度有序的纤维状 聚合物（淀粉样蛋白），类似于与非传染性淀粉样变性有关的聚集体，例如阿尔茨海默病 和帕金森病，或多聚谷氨酰胺疾病，如亨廷顿病。机制 人们对淀粉样蛋白的清除知之甚少。 我们和其他小组表明，酵母中的朊病毒繁殖是通过随后的循环发生的 由伴侣蛋白介导的聚合物断裂和生长。大细胞学积累 可检测到的朊病毒蛋白或其他淀粉样蛋白的聚集结构（包涵体） 在某些条件下在酵母中观察到这种现象，有时与细胞毒性有关。它证明了 我们的数据表明，一些包涵体与肌动蛋白细胞骨架网络相互作用，参与内吞作用和 将内吞囊泡运输至液泡。 建议：1）包涵体代表朊病毒生成或朊病毒消除的中间体 途径，2）朊病毒的繁殖受到活跃增殖之间的动态平衡的调节。 朊病毒单位和包涵体不能有效繁殖。伴侣、蛋白水解系统、 细胞骨架网络和贩运途径通过改变朊病毒的传播和清除来调节 包涵体和增殖的朊病毒单位之间的平衡。我们对下一个预算期的建议是 旨在测试基于此通用模型的特定预测。 该项目的具体目标将具体解决伴侣、蛋白水解途径、 朊病毒蛋白生成和清除中的细胞骨架网络和细胞内运输途径 聚合体。总而言之，这些实验的结果将揭示清除机制 酵母细胞中聚集的淀粉样蛋白 与公共卫生的相关性：哺乳动物朊病毒疾病和许多其他淀粉样变性是致命的 无法治愈的。哺乳动物朊病毒疾病，如“疯牛病”和麋鹿和麋鹿的慢性消耗病 鹿，由于有可能传播给受感染的人类，因此对健康构成重大威胁 肉。一些淀粉样蛋白疾病，例如阿尔茨海默氏病，广泛存在且与年龄相关，因此 随着其他疾病的根除和环境的改善，它们的重要性将进一步增强。 人类的平均寿命。这项研究将进一步建立酵母作为模型 制定对抗朊病毒和其他有毒物质积累和传播的策略 淀粉样蛋白。