Oligopeptide Repeats and Prion Propagation

寡肽重复和朊病毒传播

• 批准号: 8203932
• 负责人: Christine Ricalo Langlois
• 金额: $ 2.79万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8203932
• 关键词: Address; Adopted; Affect; Appearance; Beryllium; Biological Assay; Cells; Characteristics; Clinical; Complex; Development; Disease; Disease Progression; Elements; Environment; Event; Goals; Huntington Disease; In Vitro; Indium; Individual; Knowledge; Lead; Link; Maintenance; Mammals; Molecular Chaperones; Molecular Conformation; N-terminal; Nature; Neurodegenerative Disorders; Oligopeptides; Pathway interactions; Phenotype; Physiology; Prion Diseases; Prions; Process; Protein Structure Initiative; Proteins; Reading; Research; Role; Saccharomyces cerevisiae; Series; System; Terminator Codon; Testing; Thermodynamics; Variant; Work; Yeasts; daughter cell; in vivo; insight; novel therapeutics; physical property; protein aggregation; protein folding; protein misfolding; sup35; transmission process

DESCRIPTION (provided by applicant): The misfolding normal, cellular encoded proteins and their subsequent aggregation has emerged as a common mechanism underlying several neurodegenerative diseases in mammals, including Huntington's and the Transmissible Spongiform Encephalopathies (prion diseases). A key event in this process is the efficient amplification of misfolded form, which occurs when existing aggregates direct the conversion of normal protein to a like state. This autocatalytic misfolding in influenced by sequence elements within the implicated proteins, such as repeated elements that modulate both the appearance and persistence of the misfolded form. Despite their importance, the mechanism(s) by which these sequence elements influence the autocatalytic misfolding pathway is currently unknown. The goal of this proposal is to address this significant gap in knowledge. For this work, we will use the Sup35/[PSI+] prion system in the yeast S. cerevisiae. The Sup35 protein contains five and a half imperfect copies of an oligopeptide repeat. Deletion of one or more full repeats completely abolishes the autocatalytic misfolding of Sup35, while expansion of the repeat region increases the propensity of cells to adopt and propagate this form. We hypothesize that the oligopeptide repeats alter the efficiency of discrete steps in the Sup35 misfolding pathway and thereby the stability of the prion-associated phenotype by impacting the nature of Sup35 physical interactions. To test this hypothesis, we will identify the step(s) in the Sup35 autocatalytic misfolding pathway that are altered by variation in the number of repeats and impact of these variations on Sup35 interactions with itself and other cellular factors. By understanding how specific sequence elements modulate the protein folding environment in vivo, we will begin to understand how they contribute to both the normal cellular state and the corresponding disease state. Understanding how these sequence elements can modulate protein folding pathways within the context of the cellular environment will provide insight into how protein misfolding diseases are initiated and maintained. PUBLIC HEALTH RELEVANCE: Several neurodegenerative diseases, including Huntington's disease and the Transmissible Spongiform Enchephalopathies (prion diseases) have been linked to a unique mechanism in which a normally encoded cellular protein adopts an altered conformation, leading to protein aggregation and the diseased state. Specific sequence elements in the implicated proteins have been shown to be necessary for the propagation of the disease state. Understanding how these elements modulate the protein folding pathways that lead to disease can lead to new therapeutic insights and targets for the treatment of these diseases.

描述（由申请人提供）：错误折叠的正常细胞编码蛋白质及其随后的聚集已经成为哺乳动物中几种神经变性疾病的常见机制，包括亨廷顿病和传染性海绵状脑病（朊病毒疾病）。这个过程中的一个关键事件是错误折叠形式的有效扩增，当现有的聚集体引导正常蛋白质转化为类似状态时，就会发生这种情况。这种自催化性错误折叠受到相关蛋白质内的序列元件的影响，例如调节错误折叠形式的外观和持久性的重复元件。尽管它们的重要性，这些序列元件影响自催化错误折叠途径的机制目前尚不清楚。本提案的目的是填补这一重大知识空白。为了这项工作，我们将在酵母S中使用Sup 35/[PSI+]朊病毒系统。啤酒。Sup 35蛋白含有五个半不完美的寡肽重复拷贝。一个或多个完整重复序列的缺失完全消除了Sup 35的自催化错误折叠，而重复序列区域的扩增增加了细胞采用和繁殖这种形式的倾向。我们假设寡肽重复序列通过影响Sup 35物理相互作用的性质，改变Sup 35错误折叠途径中离散步骤的效率，从而改变朊病毒相关表型的稳定性。为了验证这一假设，我们将确定Sup 35自催化错误折叠途径中的步骤，这些步骤因重复次数的变化而改变，以及这些变化对Sup 35与自身和其他细胞因子相互作用的影响。通过了解特定序列元件如何调节体内蛋白质折叠环境，我们将开始了解它们如何促进正常细胞状态和相应的疾病状态。了解这些序列元件如何在细胞环境的背景下调节蛋白质折叠途径，将有助于深入了解蛋白质错误折叠疾病是如何启动和维持的。 公共卫生相关性：几种神经变性疾病，包括亨廷顿病和传染性海绵状脑病（朊病毒疾病），已经与一种独特的机制有关，其中正常编码的细胞蛋白采用改变的构象，导致蛋白质聚集和疾病状态。已显示所涉及的蛋白质中的特定序列元件对于疾病状态的传播是必需的。了解这些元素如何调节导致疾病的蛋白质折叠途径，可以为治疗这些疾病带来新的治疗见解和靶点。