Investigating the prion formation of neuronal CPEB

描述(由申请人提供)：Prion是一种蛋白质，可以转变为自我永久的、具有感染性的构象，这是整个进化光谱中蛋白质共有的特性。尽管Pron及其形成的淀粉样纤维通常与导致神经退化的疾病有关，但已有研究表明，Prion也可以有益于具有多种正常生物学功能的细胞，包括细胞黏附、对环境压力的适应和皮肤色素沉着。与我们的合作者(哥伦比亚大学的Eric Kandel博士和Stowers研究所的Kausik Si博士)一起，我们假设由于海藻神经元CPEB(一种休眠mRNA的翻译激活剂)具有类病毒、自我模板的性质，对大脑学习和记忆功能至关重要的突触的变化可以长期保持。我们的目标是表征神经元CPEB的淀粉样蛋白的性质，以便产生不能转换为活性普恩构象或表现为神经元CPEB的显性-阴性版本的突变体。这些突变体随后将在酵母和高等生物体中进行体内测试，以研究它们对翻译激活和最终突触可塑性的影响。公共卫生利益：Pron蛋白及其形成的淀粉样纤维是人类神经退行性疾病的致病因子。然而，最近的研究表明，某些普恩也可能对细胞有益，或执行正常的生物功能。特别是，我们研究的类普里子蛋白nCPEB可能在突触维持中发挥关键作用。最终，我们想要证明，分子记忆是自我永久化的普恩的固有属性，可能在突触可塑性、学习和记忆中发挥作用。因此，研究nCPEB对于提高我们对对人体有害的普恩的总体认识，以及对普恩生物学有益的功能方面有新的见解都是非常重要的。鉴于我们对淀粉样蛋白的结构有初步了解的很少，利用酵母基因分析与生物物理技术相结合的能力将使我们能够为淀粉样蛋白生物学领域带来新的曙光。

DESCRIPTION (provided by applicant): Prions are proteins that can switch to self-perpetuating, infectious conformations, a property shared by proteins across the evolutionary spectrum. Although prions and the amyloid fibers they form are usually linked to diseases that often result in neurodegeneration, it has been proposed that prions can also be beneficial to the cell with diverse normal biological functions including cell-adhesion, adaptation to environmental stresses, and skin pigmentation. With our collaborators (Drs. Eric Kandel, Columbia University, and Kausik Si, Stowers Institute), we postulate that due to the prion-like, self-templating nature of Aplysia neuronal CPEB (a translational activator of dormant mRNAs) alterations of a synapse that are key to learning and memory functions of the brain can be maintained long-term. Our aim is to characterize the amyloid nature of neuronal CPEB in order to generate mutants that cannot switch into the active prion conformation or that behave as dominant-negative versions of neuronal CPEB. These mutants will then be tested in vivo in yeast and higher organisms to investigate their effects on translational activation and ultimately synaptic plasticity. Public health interest: Prion proteins and the amyloid fibers they form are best known as causative agents of neurodegenerative diseases in humans. Recent studies showed, however, that certain prions might also be beneficial to the cell or carry out normal biological functions. In particular, the prion-like protein we study, nCPEB, might play a pivotal role in synapse maintenance. Ultimately, we would like to demonstrate that the molecular memory that is an intrinsic property of self-perpetuating prions may play a role in synaptic plasticity, learning and memory. It is therefore of great importance to study nCPEB, to both enhance our general understanding of prions that are detrimental to men, and gain new insights into beneficial functional aspects of prion biology. Given that there are so few amyloids for which we have even an elementary grasp of structure, the ability to take advantage of yeast genetic analysis in combination with biophysical techniques will position us to shed new light on the field of amyloid biology.