Discovering How Cu(II)/Zn(II) Uptake by the Prion Protein Controls Structure, Function and Neurotoxicity

发现朊病毒蛋白摄取 Cu(II)/Zn(II) 如何控制结构、功能和神经毒性

• 批准号: 10612778
• 负责人: GLENN L MILLHAUSER
• 金额: $ 34.26万
• 依托单位: UNIVERSITY OF CALIFORNIA SANTA CRUZ
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10612778
• 关键词: Alzheimer' s Disease; Amyloid beta-Protein; Anatomy; Binding; Binding Proteins; Binding Sites; Biochemical; Biophysics; Brain; Central Nervous System; Cessation of life; Creutzfeldt-Jakob Syndrome; Disease; Electrophysiology (science); Fatal Familial Insomnia; Funding; Glutamate Receptor; Goals; Grant; Inherited; Ions; Kuru; Magnetic Resonance; Membrane; Metal Ion Binding; Metals; Molecular; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Pathway interactions; Peptides; Peripheral; Positioning Attribute; Post-Translational Protein Processing; PrP; PrPSc Proteins; Prion Diseases; Prions; Process; Proteins; Research Project Summaries; Resources; Role; Scrapie; Signal Transduction; Stress; Structure; Thermodynamics; Tissues; Toxic effect; Work; cytotoxicity; flexibility; neurotoxicity; protein folding; receptor; uptake

Project Summary Research into the proteins that cause neurodegenerative diseases is undergoing a remarkable transformation with the detailed identification of biochemical and biophysical pathways that drive neuron stress and death. Our work focuses on the cellular prion protein (PrPC), a ubiquitous protein of the central nervous system and peripheral tissues. Misfolding of PrPC to its scrapie form, PrPSc, causes a range of diseases including Creutzfeldt-Jakob disease (CJD), Fatal Familial Insomnia and Kuru. In addition, PrPC was recently identified as a primary receptor for Aβ peptide oligomers that drive cytotoxicity in Alzheimer’s disease. Our focus is two-fold: First, we wish to understand the function of this wide-spread protein, and second, we want to understand how aberrant signaling in prion diseases and Alzheimer’s disease leads to neurodegeneration. It is now well established that PrPC is a Cu2+/Zn2+-binding protein that controls the anatomical distribution of these essential metal ions in the brain. Through our long- standing grant GM065790-16, we have determined the coordination features of the metal ion binding sites, evaluated the detailed binding thermodynamics, and developed new concepts for understanding inherited prion diseases. Within the last few years, using magnetic resonance and electrophysiology, we uncovered an inter-domain interaction in PrPC, driven by metal ion binding, which regulates neurotoxicity. We are now positioned to pursue the molecular details of this interaction, as well as the role of varying metal ion concentrations, global protein fold, relevant post-translational modifications and disease associated mutations. In addition, it is now recognized that PrPC modulates the function of several transmembrane glutamate receptors – we wish to identify the PrPC functional domains relevant to these important interactions. Our evolving paradigm of PrPC toxicity provides a platform for understanding neurodegenerative processes in both prion and Alzheimer’s diseases. Our request for MIRA funding is to enable the resources and flexibility so that we may work efficiently in this highly important and rapidly changing field.

项目概要 对引起神经退行性疾病的蛋白质的研究正在经历显着的进展 通过详细识别驱动的生化和生物物理途径进行转化 神经元应激和死亡。我们的工作重点是细胞朊病毒蛋白 (PrPC)，这是一种普遍存在的 中枢神经系统和周围组织的蛋白质。 PrPC 错误折叠为痒病 PrPSc 形式可引起一系列疾病，包括克雅氏病 (CJD)、致命的 家族性失眠和库鲁病。此外，PrPC 最近被确定为主要受体 Aβ 肽寡聚物在阿尔茨海默病中发挥细胞毒性。我们的重点有两个：第一， 我们希望了解这种广泛传播的蛋白质的功能，其次，我们想要 了解朊病毒疾病和阿尔茨海默病中的异常信号如何导致 神经变性。现在已经确定 PrPC 是一种 Cu2+/Zn2+ 结合蛋白， 控制这些必需金属离子在大脑中的解剖分布。通过我们长期的 长期授权GM065790-16，我们确定了金属离子的配位特征 结合位点，评估了详细的结合热力学，并开发了新概念 了解遗传性朊病毒疾病。近年来，利用磁共振 和电生理学，我们发现了 PrPC 中由金属离子驱动的域间相互作用 结合，调节神经毒性。我们现在的定位是追求分子细节 这种相互作用，以及不同金属离子浓度、整体蛋白质折叠的作用， 相关的翻译后修饰和疾病相关突变。另外，现在是 认识到 PrPC 调节多种跨膜谷氨酸受体的功能 – 我们希望确定与这些重要相互作用相关的 PrPC 功能域。我们的 PrPC 毒性的演变范式为理解神经退行性疾病提供了一个平台 朊病毒和阿尔茨海默病的过程。我们对 MIRA 资金的请求是为了 资源和灵活性，使我们能够在这一高度重要且迅速的领域高效工作 改变领域。