A Prion Reveals Complex Traits and Phenotypic Diversity

描述(由申请人提供)：酵母Sup35蛋白是一种翻译终止因子，具有形成自我永续有序聚集体(Prion[PSI])的不同寻常的能力，导致翻译终止的保真度发生可遗传的变化。在不同的遗传背景中，[PSI]产生不同的表型集，改变不同条件下的生长和生存。有几个问题仍有待解决，以了解这种普里恩元素的全部生物学意义。1)[PSI]Prion揭示的表型多样性的分子本质是什么？对依赖于[PSI]的特征的分析表明，它们既是无意义抑制的结果，也是蛋白质聚集的结果。2)最近的数据表明，一些依赖于[PSI]的表型是复杂的性状。这些性状需要许多因素的组合，并提供了一个可行的模型来研究环境条件与遗传和表观遗传因素相结合的表型效应。在一个这样的特征中，形态上依赖于Prion的改变，一个贡献的途径已经被确定，无义抑制，蛋白质聚集，以及产生表型的环境的相互作用将被调查。3)这种表观遗传因素是如何调节的？这种蛋白的生物学后果是什么？解决这些问题将有助于更好地了解[PSI]对酵母种群生物学、生存和进化的影响。这项研究将剖析[PSI]元素的机制性质，并确定该蛋白是否为表型可塑性提供了一种独特的机制，可能会促进复杂性状的进化。此外，这项工作可能会为丰富的普恩生物学和这种表观遗传调控的生理影响提供更多的见解。此外，这种酵母蛋白提供了一个模型系统来理解触发蛋白质聚集的环境线索，这对于理解与几种神经退行性疾病相关的蛋白质错误折叠的启动具有广泛的意义。

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.