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.

王室是自我延续的蛋白质同工型，在哺乳动物中引起致命的神经退行性疾病 人类并控制酵母中的遗传特征。大多数已知迄今已知的葡萄纤维形成 聚合物（淀粉样蛋白），类似于参与不可转移淀粉样蛋白的聚集体，例如阿尔茨海默氏症 和帕金森氏病，或亨廷顿氏病等聚谷氨酸疾病。机制 淀粉样蛋白的清除率很少。 我们和其他群体表明，酵母中的prion传播是通过随后的周期发生的 聚合物分裂和生长，由伴侣蛋白介导。大细胞学的积累 可检测的prion蛋白或其他淀粉样蛋白蛋白的可检测的聚集结构（包容体）是 在某些条件下在酵母中观察到，有时与细胞毒性有关。它证明了 我们一些包含物体与肌动蛋白细胞骨架网络相互作用的数据，涉及内吞和 将内吞囊泡运输到液泡中。 有人提出：1）包容物体代表王室产生或消除王室中的中间体 途径和2）prion传播受主动增殖之间的动态平衡调节 prion单位和包容物体无法有效地传播。伴侣，蛋白水解系统， 细胞骨架网络和运输途径通过转移来调节prion的传播和清除率 包容体和增殖的prion单位之间的平衡。我们在下一个预算期间的建议是 旨在基于此通用模型测试特定预测。 该项目的具体目标将专门解决伴侣，蛋白水解途径的作用， 细胞骨架网络和细胞内贩运途径的产生和清除蛋白质的清除率 聚合。综上所述，这些实验的结果将发现清除机制 酵母细胞中的聚集的淀粉样蛋白蛋白 与公共卫生相关：哺乳动物的病毒疾病和许多其他淀粉样蛋白是致命的， 无法治愈。哺乳动物的儿童疾病，例如“疯牛”疾病和麋鹿的慢性浪费疾病 鹿，代表着重大的健康威胁，因为他们可能会向被感染的人类传播 肉。一些淀粉样蛋白疾病，例如阿尔茨海默氏病，是广泛的和年龄依赖的，因此 它们的重要性将与消除其他疾病并改善的同时增长 人口的平均寿命。这项研究将进一步建立酵母作为模型 制定策略抵消王室和其他有毒的策略 淀粉样蛋白。