Investigating the prion formation of neuronal CPEB

描述（由申请人提供）：朊病毒是一种可以转变为自我延续、感染性构象的蛋白质，这是整个进化谱中蛋白质所共有的一种特性。虽然朊病毒和它们形成的淀粉样蛋白纤维通常与经常导致神经变性的疾病有关，但已经提出朊病毒也可以有益于具有多种正常生物功能的细胞，包括细胞粘附，适应环境压力和皮肤色素沉着。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Aparosia神经元CPEB（休眠mRNA的翻译激活剂）的朊病毒样自模板性质，突触的改变是大脑学习和记忆功能的关键，可以长期维持。我们的目的是表征神经元CPEB的淀粉样蛋白性质，以产生不能转换为活性朊病毒构象或表现为显性阴性的神经元CPEB版本的突变体。然后，这些突变体将在酵母和高等生物体内进行测试，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：朊病毒蛋白和它们形成的淀粉样纤维是人类神经退行性疾病的病原体。然而，最近的研究表明，某些朊病毒也可能对细胞有益或执行正常的生物功能。特别是，我们研究的朊病毒样蛋白，nCPEB，可能在突触维持中发挥关键作用。最后，我们想证明，分子记忆，这是一个内在的性质，自我永存朊病毒可能发挥作用，突触可塑性，学习和记忆。因此，研究nCPEB非常重要，既可以增强我们对朊病毒对男性有害的一般理解，又可以获得朊病毒生物学有益功能方面的新见解。鉴于我们对淀粉样蛋白结构的基本了解非常少，因此结合生物物理技术利用酵母遗传分析的能力将使我们能够在淀粉样蛋白生物学领域获得新的认识。

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.