Genetic Study of the Yeast Prion-Interacting Proteins

Prion是一种自我延续的蛋白质亚型，可导致哺乳动物患上致命的神经退行性疾病 并在酵母中控制可遗传的特征。到目前为止，已知的大多数Prion由高度有序的纤维组成 聚合物(淀粉样蛋白)，类似参与非遗传性淀粉样变性的聚集体，如阿尔茨海默氏症 以及帕金森氏症，或亨廷顿氏病等多谷氨酰胺疾病。机制： 对淀粉样蛋白的清除知之甚少。 我们和其他研究小组发现，在酵母菌中，病毒的繁殖是通过随后的循环 由伴侣蛋白介导的聚合物裂解和生长。细胞学上的大细胞积聚 Pron蛋白或其他淀粉样蛋白的可检测聚集结构(包涵体)是 在某些条件下在酵母中观察到，有时与细胞毒性有关。它通过以下方式进行了演示 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 将内吞小泡运输到液泡。 我们认为：1)包涵体代表了病毒产生或消除的中间产物。 路径，以及2)Pron的传播受活跃的增殖之间的动态平衡调节 Pron单位和包涵体不能有效繁殖。伴侣，蛋白分解系统， 细胞骨架网络和运输途径通过转移 包涵体和增殖的普恩单位之间的平衡。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涉及伴侣的作用，蛋白质分解途径， PrP蛋白产生和清除过程中的细胞骨架网络和细胞内转运途径 集合体。综上所述，这些实验结果将揭示药物清除的机制。 酵母细胞中聚集的淀粉样蛋白 与公共卫生相关：哺乳动物的Pron疾病和许多其他淀粉样变性是致命的和 不治之症。哺乳动物的Pron病，如疯牛病和麋鹿的慢性衰减病 鹿是一个重大的健康威胁，因为它们有可能传播给感染了病毒的人。 肉。一些淀粉样病，如阿尔茨海默氏病，很普遍，而且与年龄有关，因此 在根除其他疾病和改善人类健康状况的同时，它们的重要性将进一步增强。 人类人口的平均寿命。这项研究将进一步建立酵母菌作为模型 对抗Pron和其他有毒物质积累和繁殖的策略的发展 淀粉样蛋白。

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.