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.

该应用的总体目标是了解prions造成损害的机制突触，建立和维持中枢神经系统中的自发感染。我们也希望发展根据我们对分子和细胞的了解，这些疾病的药理学疗法疾病过程的基础机制。虽然prion传播的分子模型模型，但现在，PRPC转化为传染性PRPSC，现在已被广泛接受，是prions的机制实际上是由于神经退行性的神秘而已。现在有大量证据表明细胞 - 表面PRPC介导了PRPSC的许多神经毒性作用，可能是作为结合PRPSC的受体在Prion转换过程的第一步中。但是，这是如何启动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未知。我们在上一个赠款周期中完成的工作为此提供了关键的见解通过定义PRPC/NMDAR/p38 MAPK信号通路，介导PRPSC的最早影响突触毒性。基于结构分析和功能测定的组合，我们提出了 PRPC的N末端结构域用作有毒效应子的模型，该模型受特定对接调节的模型与C末端结构域的相互作用。这种分子内相互作用的人工破坏会导致多种多样细胞和转基因模型中的有毒活性。在此续订应用中，我们首先提出，以阐明如何在细胞表面。其次，我们计划剖析被prions激活的细胞内信号传导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王室感染。我们预计这里提出的研究将为您提供强大的见解由毒性蛋白引起的多种神经退行性疾病常见的生物学机制大脑中的聚集物，并将导致发现共享的治疗方法对待他们。