A Prion Reveals Complex Traits and Phenotypic Diversity

朊病毒揭示了复杂的特征和表型多样性

• 批准号: 7541817
• 负责人: HEATHER L TRUE-KROB
• 金额: $ 29.13万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-01 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7541817
• 关键词: Address; Affect; Alzheimer' s Disease; Architecture; Biological; Biological Models; Biology; Cells; Complex; Coupled; Cues; Data; Disease; Elements; Environment; Epigenetic Process; Evolution; Gene Expression; Genetic; Goals; Growth; Huntington Disease; Inherited; Investigation; Light; Mediating; Modeling; Molecular; Morphology; Nature; Neurodegenerative Disorders; Organism; Parkinson Disease; Pathogenesis; Pathway interactions; Phenotype; Physiological; Play; Population Biology; PrP; Prion Diseases; Prions; Process; Protein Structure Initiative; Proteins; Reading; Regulation; Research; Role; Route; Terminator Codon; Translations; Variant; Virulence; Work; Yeasts; base; fitness; insight; loss of function; prion hypothesis; protein aggregate; protein aggregation; protein misfolding; sup35; termination factor; trait; transmission process; yeast prion

DESCRIPTION (provided by applicant): The yeast Sup35 protein is a translation termination factor with the unusual capacity to form a self-perpetuating ordered aggregate (the prion [PSI+]), resulting in heritable changes in the fidelity of translation termination. In different genetic backgrounds [PSI+] produces distinct sets of phenotypes, altering growth and survival in diverse conditions. Several questions remain to be addressed to understand the full biological implications of this prion element. 1) What is the molecular nature of the phenotypic diversity revealed by the [PSI+] prion? Analyses of the [PSI+]-dependent traits suggest that they result from both nonsense suppression and protein aggregation. 2) Recent data suggests that several [PSI+] - dependent phenotypes are complex traits. These traits require a combination of many factors and provide a viable model to investigate the phenotypic effects of environmental conditions coupled with both genetic and epigenetic factors. In one such trait, a prion dependent alteration in morphology, a contributing pathway has been identified, and the interplay of nonsense suppression, protein aggregation, and the environment that produces the phenotype will be investigated. 3) How is this epigenetic element regulated? What are the biological consequences of this prion? Addressing these questions will allow for a greater understanding of the impact of [PSI+] on population biology, survival, and evolution of yeast. This research will dissect the mechanistic nature of the [PSI+] element and determine if this prion provides a unique mechanism for phenotypic plasticity that might promote the evolution of complex traits. Moreover, this work may provide additional insights into the wealth of prion biology and the physiological impact of this type of epigenetic regulation. Furthermore, this yeast prion provides a model system to understand the environmental cues that trigger protein aggregation, which has broad implications in understanding the initiation of protein misfolding associated with several neurodegenerative disorders.

描述（由申请人提供）：酵母Sup35蛋白是一种翻译终止因子，具有形成自我延续的有序聚集体（朊病毒[PSI+]）的异常能力，导致翻译终止保真度的遗传变化。在不同的遗传背景下，[PSI+]产生不同的表型，改变不同条件下的生长和存活。要了解这种朊病毒元素的全部生物学意义，仍有几个问题有待解决。1) [PSI+]朊病毒所揭示的表型多样性的分子性质是什么？对[PSI+]依赖性性状的分析表明，它们是无义抑制和蛋白质聚集的结果。2)最近的数据表明，几种[PSI+]依赖性表型是复杂的性状。这些性状需要多种因素的共同作用，为研究环境条件与遗传和表观遗传因素耦合的表型效应提供了可行的模型。在一个这样的性状中，形态上的朊病毒依赖性改变，已经确定了一个贡献途径，并且将研究无义抑制，蛋白质聚集和产生表型的环境的相互作用。3)这个表观遗传因子是如何调控的？这种朊病毒的生物学后果是什么？解决这些问题将使我们更好地了解[PSI+]对酵母种群生物学、生存和进化的影响。本研究将剖析[PSI+]元素的机制性质，并确定该朊病毒是否提供了一种独特的表型可塑性机制，从而可能促进复杂性状的进化。此外，这项工作可能为丰富的朊病毒生物学和这种类型的表观遗传调控的生理影响提供额外的见解。此外，该酵母朊病毒提供了一个模型系统来理解触发蛋白质聚集的环境线索，这对理解与几种神经退行性疾病相关的蛋白质错误折叠的起始具有广泛的意义。