Mechanisms of Prion Protein Toxicity

朊病毒蛋白毒性机制

基本信息

批准号：
10298636
负责人：
DAVID A HARRIS
金额：
$ 78.61万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10298636
关键词：
1-Phosphatidylinositol 3-Kinase Address Alzheimer&apos s Disease Amino Acids Amyloid beta-Protein Animals Applications Grants Binding Biological Biological Assay Blood Brain C-terminal Cell model Cell surface Cells Chemicals Combined Modality Therapy Cytoplasm Development Disease Docking Drug Targeting Enzymes Food Safety Frontotemporal Dementia Functional disorder Generations Genetic Transcription Goals Grant Human Infection Knowledge Label Ligands Lipids Mass Spectrum Analysis Mediating Membrane Microscopy Modeling Molecular Morphology Mus N-terminal Nerve Degeneration Neurodegenerative Disorders Neurons Organ Parkinson Disease Pathogenesis Pathway interactions Pharmaceutical Preparations Pharmacology PrP PrPSc Proteins Prion Diseases Prions Process Property Protein Kinase Protein Kinase C Proteins Public Health Resolution Role Signal Pathway Signal Transduction Structure Synapses Synaptic Transmission System Tauopathies Technology Testing Therapeutic Toxic effect Transgenic Model Work alpha synuclein base calmodulin-dependent protein kinase II cellular targeting crosslink design flexibility glycogen synthase kinase 3 beta insight nerve damage neuron loss neurotoxic neurotoxicity novel novel therapeutic intervention p38 MAPK Signaling Pathway protein aggregation receptor receptor binding sigma-1 receptor

项目摘要

The overall goal of this application is to understand the mechanisms by which prions cause damage to synapses, and establish and maintain a self-propagating infection in the CNS. We also wish to develop pharmacologic therapies for these disorders based on our knowledge of the molecular and cellular mechanisms underlying the disease process. Although the molecular templating model for prion propagation, in which PrPC is converted into infectious PrPSc, is now widely accepted, the mechanisms by which prions actually cause neurodegeneration have remained mysterious. There is now considerable evidence that cell- surface PrPC mediates many of the neurotoxic effects of PrPSc, likely by serving as a receptor that binds PrPSc during the first step of the prion conversion process. However, how this initiates downstream toxic signals in the cytoplasm, and how these signals alter synaptic structure or function were largely unknown. The work we have accomplished during the previous grant cycle has provided key insights into this issue by defining a PrPC/NMDAR/p38 MAPK signaling pathway that mediates the earliest effects of PrPSc synaptotoxicity. Based on a combination of structural analysis and functional assays, we have proposed a model in which the N-terminal domain of PrPC serves as a toxic effector that is regulated by specific docking interactions with the C-terminal domain. Artificial disruption of this intramolecular interaction results in a variety of toxic activities in cellular and transgenic models. In this renewal application, we propose, first, to elucidate how prion synaptotoxic signaling is initiated at the cell surface. Second, we plan to dissect the intracellular signaling cascades that are activated by prions, and how they result in synaptic dysfunction. Third, we will investigate the mechanisms by which cells establish and maintain prion infection. We anticipate that the studies proposed here will provide powerful insights into biological mechanisms that are common to multiple neurodegenerative disorders caused by toxic protein aggregates in the brain, and will lead to the discovery of shared therapeutic approaches that can be used to treat them.

该应用程序的总体目标是了解朊病毒造成损害的机制突触，并在中枢神经系统中建立并维持自我传播的感染。我们也希望发展基于我们对分子和细胞的了解，对这些疾病进行药物治疗疾病过程的潜在机制。虽然朊病毒传播的分子模板模型， PrPC 转化为传染性 PrPSc 的过程现已被广泛接受，朊病毒的机制神经退行性变的真正原因仍然是个谜。现在有大量证据表明细胞表面 PrPC 可能通过作为结合 PrPSc 的受体介导 PrPSc 的许多神经毒性作用在朊病毒转化过程的第一步中。然而，这如何引发下游有毒信号细胞质以及这些信号如何改变突触结构或功能在很大程度上是未知的。我们在上一个资助周期完成的工作为这个问题提供了重要的见解通过定义介导 PrPSc 最早效应的 PrPC/NMDAR/p38 MAPK 信号通路突触毒性。基于结构分析和功能分析的结合，我们提出了该模型中 PrPC 的 N 端结构域作为毒性效应子，通过特异性对接进行调节与 C 末端结构域的相互作用。人为破坏这种分子内相互作用会导致多种细胞和转基因模型中的毒性活性。在此更新申请中，我们建议首先阐明朊病毒突触毒性信号传导是如何在细胞表面。其次，我们计划剖析由朊病毒激活的细胞内信号级联，以及它们如何导致突触功能障碍。第三，我们将研究细胞建立的机制。并维持朊病毒感染。我们预计这里提出的研究将提供强有力的见解有毒蛋白质引起的多种神经退行性疾病的常见生物学机制聚集在大脑中，并将导致发现可用于对待他们。