Investigating the prion formation of neuronal CPEB

研究神经元 CPEB 的朊病毒形成

• 批准号: 7513406
• 负责人: Sven Uwe Heinrich
• 金额: $ 5.29万
• 依托单位: WHITEHEAD INSTITUTE FOR BIOMEDICAL RES
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-10-01 至 2010-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7513406
• 关键词: Affect; Amyloid; Amyloid fibers; Aplysia; Binding Proteins; Biological Assay; Biological Process; Biology; Brain; Cell Adhesion; Cells; Chromosome Pairing; Class; Disease; Dominant-Negative Mutation; Fiber; Human; In Vitro; Institutes; Learning; Light; Link; Localized; Maintenance; Memory; Molecular; Molecular Conformation; Nature; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Organism; Play; Positioning Attribute; Prions; Property; Protein Biosynthesis; Proteins; Public Health; Role; Shapes; Skin Pigmentation; Stress; Structure; Synapses; Synaptic plasticity; Techniques; Testing; Translational Activation; Translations; Universities; Yeasts; amyloid structure; base; genetic analysis; grasp; in vivo; insight; interest; men; mutant; yeast genetics

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.

描述（由申请人提供）：朊病毒是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共有的特性。尽管朊病毒及其形成的淀粉样蛋白纤维通常与导致神经变性的疾病有关，但有人提出，朊病毒也可能对具有多种正常生物功能的细胞有益，包括细胞粘附、适应环境压力和皮肤色素沉着。我们与合作者（哥伦比亚大学的 Eric Kandel 博士和斯托尔斯研究所的 Kausik Si 博士）一起推测，由于海兔神经元 CPEB（休眠 mRNA 的翻译激活剂）具有类似朊病毒的自模板性质，突触的改变对于大脑的学习和记忆功能至关重要，因此可以长期维持。我们的目标是表征神经元 CPEB 的淀粉样蛋白性质，以便产生不能转变为活性朊病毒构象或表现为神经元 CPEB 显性失活版本的突变体。然后将在酵母和高等生物体内测试这些突变体，以研究它们对翻译激活和最终突触可塑性的影响。公共健康利益：朊病毒蛋白及其形成的淀粉样纤维被认为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发挥正常的生物功能。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。最终，我们想证明，分子记忆是自我延续的朊病毒的固有特性，可能在突触可塑性、学习和记忆中发挥作用。因此，研究 nCPEB 非常重要，既可以增强我们对对男性有害的朊病毒的一般了解，又可以对朊病毒生物学的有益功能方面获得新的见解。鉴于我们对淀粉样蛋白的结构有基本了解的数量如此之少，利用酵母遗传分析与生物物理技术相结合的能力将使我们为淀粉样蛋白生物学领域带来新的认识。