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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.

这个应用程序的总体目标是了解Pron引起损害的机制突触，并在中枢神经系统中建立和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知识对这些疾病的药物治疗疾病过程的潜在机制。尽管用分子模板模型来描述普恩病毒的传播， PrPC被转化为具有感染性的PrPSc，现在已经被广泛接受，PrPc的机制是实际上导致神经退行性变的原因仍然是个谜。现在有相当多的证据表明细胞- 表面PrPC可能通过作为受体与PrPSc结合而介导PrPSc的许多神经毒性作用在Prion转化过程的第一步。然而，这是如何引发下游有毒信号的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。我们在前一个赠款周期中完成的工作为这一问题提供了关键的见解通过定义PrPC/NMDAR/p38 MAPK信号通路，介导PrPSc的最早效应突触毒性。基于结构分析和功能分析的结合，我们提出了一种 PrPC的N-末端结构域作为受特定对接调节的毒性效应因子的模型与C-末端结构域的相互作用。这种分子内相互作用的人为破坏导致了各种在细胞和转基因模型中的毒性活动。在这一更新应用中，我们建议，首先阐明蛋白突触毒性信号是如何在细胞表面。其次，我们计划剖析被普鲁恩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保持普恩病毒的感染。我们预计，这里提出的研究将为有毒蛋白引起的多种神经退行性疾病的共同生物学机制聚集在大脑中，并将导致发现共同的治疗方法，可用于给他们治病。