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

项目摘要 对导致神经退行性疾病的蛋白质的研究正在进行一项引人注目的研究 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内的蛋白(PrPC)，一种普遍存在的 中枢神经系统和周围组织的蛋白质。PrPC错误折叠到它的抓痕 形式，PrPSc，导致一系列疾病，包括克雅氏病(CJD)，致命 家族性失眠和库鲁。此外，PrPC最近被确定为一种主要的受体 一种在阿尔茨海默病中驱动细胞毒性的β肽低聚物。我们的重点是两个方面：第一， 我们希望了解这种广泛分布的蛋白质的功能，第二，我们想要 了解Pron疾病和阿尔茨海默病中的异常信号如何导致 神经退行性变。现在已经确定PrPC是一种铜/锌结合蛋白，它可以 控制这些基本金属离子在大脑中的解剖分布。通过我们漫长的- 常批GM065790-16，测定了金属离子的配位特征 结合部位，评估了详细的结合热力学，并为 了解遗传性普恩病毒疾病。在过去的几年里，利用磁共振 在电生理学方面，我们发现PrPC中存在由金属离子驱动的域间相互作用 结合，它调节神经毒性。我们现在可以追踪分子的细节了 这种相互作用，以及不同金属离子浓度的作用，全球蛋白质折叠， 相关的翻译后修饰和疾病相关突变。此外，它现在是 认识到PrPC调节几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毒性的进化范式为理解神经退行性变提供了平台 Prion和阿尔茨海默氏病的过程。我们为Mira提供资金的请求是为了 资源和灵活性使我们可以在这一非常重要和迅速的情况下高效工作 正在更改字段。

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.