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经历一个显着的 通过详细识别生物化学和生物物理途径， 神经元应激和死亡。我们的工作重点是细胞朊蛋白（PrPC），一种普遍存在的 中枢神经系统和周围组织的蛋白质。PrPC的错误折叠导致其瘙痒症 形式，PrPSc，导致一系列疾病，包括克雅氏病（CJD），致命的 家族性疾病和库鲁病。此外，PrPC最近被鉴定为用于以下的主要受体： Aβ肽寡聚体在阿尔茨海默病中驱动细胞毒性。我们的重点有两个：第一， 我们希望了解这种广泛分布的蛋白质的功能，第二，我们希望 了解朊病毒疾病和阿尔茨海默病中的异常信号是如何导致 神经变性现在已经确定PrPC是一种Cu 2 +/Zn 2+结合蛋白， 控制着这些重要金属离子在大脑中的解剖分布。在我们漫长的- 利用GM 065790 -16长期资助项目，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，并为 了解遗传性朊病毒疾病在过去的几年里，利用磁共振技术 和电生理学，我们发现PrPC中的结构域间相互作用，由金属离子驱动， 结合，调节神经毒性。我们现在可以追踪分子细节 这种相互作用，以及不同的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的突变。此外，现在 认识到PrPC调节几种跨膜谷氨酸受体的功能- 我们希望鉴定与这些重要相互作用相关的PrPC功能结构域。我们 PrPC毒性的演变范式为理解神经退行性疾病提供了平台 朊病毒和阿尔茨海默病的过程。我们对MIRA资金的要求是使 资源和灵活性，以便我们能够在这一非常重要和迅速的领域有效地工作。 换场

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.