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: 10396527
• 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/10396527
• 关键词: Alzheimer' s Disease; Amyloid beta-Protein; Anatomy; Binding; Binding Proteins; Binding Sites; Biochemical; Biophysics; Brain; Cessation of life; Creutzfeldt-Jakob Syndrome; Disease; Electrophysiology (science); Fatal Familial Insomnia; Funding; Glutamate Receptor; Goals; Grant; Inherited; Ions; Kuru; Magnetic Resonance; Metal Ion Binding; Metals; Molecular; Mutation; Nerve Degeneration; Neuraxis; 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.

项目摘要 对引起神经退行性疾病的蛋白质进行的研究正在进行出色 通过详细识别驱动生化和生物物理途径的详细识别 神经元的压力和死亡。我们的工作着重于无处不在的细胞prion蛋白（PRPC） 中枢神经系统和周围组织的蛋白质。将PRPC折叠到其crapie PRPSC形式引起一系列疾病 家族失眠和库鲁。此外，最近将PRPC确定为主要接收器 在阿尔茨海默氏病中驱动细胞毒性的Aβ肽寡聚物。我们的重点是两个方面：首先 我们希望理解这种广泛蛋白质的功能，其次，我们希望 了解病毒疾病和阿尔茨海默氏病的异常信号如何导致 神经变性。现在已经很好地确定PRPC是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。通过我们的长期 站立授予GM065790-16，我们确定了金属离子的协调特征 绑定位点，评估详细的结合热力学，并为 了解继承的王室疾病。在过去的几年中，使用磁共振 和电生理学，我们发现了由金属离子驱动的PRPC中的域间相互作用 结合，调节神经毒性。我们现在可以追求分子细节 这种相互作用以及不同金属离子浓度，全局蛋白质折叠的作用， 相关的翻译后修饰和疾病相关的突变。另外，现在是 认识到PRPC调节了几个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毒性不断发展的范式为理解神经退行性的平台提供了一个平台 病毒和阿尔茨海默氏病的过程。我们要求Mira资金的要求是​​启用 资源和灵活性，以便我们可以在这一非常重要的和迅速的情况下有效地工作 更改字段。