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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：
10665723
负责人：
DAVID A HARRIS
金额：
$ 78.3万
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/10665723
关键词：
Address Alzheimer&apos s Disease Amino Acids Amyloid beta-Protein Animals Applications Grants Binding Biological Biological Assay Blood Brain C-terminal Cell surface Cells Chemicals Combined Modality Therapy Cytoplasm Development Disease Docking Drug Targeting Enzymes Food Safety Frontotemporal Dementia Functional disorder Generations Genetic Transcription Genomics Goals Grant Human Infection Knowledge Label Ligands Lipids Mass Spectrum Analysis Mediating Membrane Modeling Molecular Morphology Mus N-terminal Nerve Degeneration Neurodegenerative Disorders Neurons Organ PIK3CG gene Parkinson Disease Pathogenesis Pathway interactions Pharmaceutical Preparations PrP PrPSc Proteins Prion Diseases Prions Process Property Protein Kinase Protein Kinase C Proteins Public Health Role Signal Pathway Signal Transduction Structure Synapses Synaptic Transmission System Tauopathies Technology Testing Therapeutic Toxic effect Transgenic Model Work alpha synuclein 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 pharmacologic protein aggregation receptor receptor binding sigma-1 receptor superresolution microscopy tau Proteins

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.

本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和维持自我传播感染。我们还希望发展这些疾病的药物治疗是基于我们对分子和细胞的知识，疾病过程的潜在机制。尽管朊病毒传播的分子模板模型， PrPC转化为传染性PrPSc的机制，现在被广泛接受，朊病毒神经退化的真正原因仍然是个谜现在有大量证据表明细胞- 表面PrPC介导PrPSc的许多神经毒性作用，可能是作为结合PrPSc的受体在朊病毒转化过程的第一步。然而，这如何启动下游有毒信号，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。我们在上一个赠款周期完成的工作为这一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测定的结合，我们提出了一种新的方法， PrPC的N-末端结构域作为毒性效应子，受特异性对接调节的模型与C-末端结构域的相互作用。人为破坏这种分子内相互作用，在细胞和转基因模型中的毒性活动。在这个更新的申请中，我们建议，首先，阐明朊病毒突触毒性信号是如何启动的，细胞表面。其次，我们计划剖析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，毒性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，并将导致发现共享的治疗方法，可用于对待他们。

项目成果

期刊论文数量（31）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Intrinsic toxicity of the cellular prion protein is regulated by its conserved central region.

细胞朊病毒蛋白的内在毒性由其保守的中心区域调节。

DOI：
10.1096/fj.201902749rr
发表时间：
2020
期刊：
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
影响因子：
0
作者：
Roseman,GrahamP;Wu,Bei;Wadolkowski,MarkA;Harris,DavidA;Millhauser,GlennL
通讯作者：
Millhauser,GlennL

Synthetic Prions Provide Clues for Understanding Prion Diseases.

合成朊病毒为了解朊病毒疾病提供了线索。

DOI：
10.1016/j.ajpath.2015.12.005
发表时间：
2016
期刊：
The American journal of pathology
影响因子：
0
作者：
Imberdis,Thibaut;Harris,DavidA
通讯作者：
Harris,DavidA

A Neuronal Culture System to Detect Prion Synaptotoxicity.

DOI：
10.1371/journal.ppat.1005623
发表时间：
2016-05
期刊：
PLoS pathogens
影响因子：
6.7
作者：
Fang C;Imberdis T;Garza MC;Wille H;Harris DA
通讯作者：
Harris DA

Prions activate a p38 MAPK synaptotoxic signaling pathway.

DOI：
10.1371/journal.ppat.1007283
发表时间：
2018-09
期刊：
PLoS pathogens
影响因子：
6.7
作者：
Fang C;Wu B;Le NTT;Imberdis T;Mercer RCC;Harris DA
通讯作者：
Harris DA

A nine amino acid domain is essential for mutant prion protein toxicity.

九个氨基酸结构域对于突变朊病毒蛋白的毒性至关重要。

DOI：
10.1523/jneurosci.1243-11.2011
发表时间：
2011
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
0
作者：
Westergard,Laura;Turnbaugh,JessieA;Harris,DavidA
通讯作者：
Harris,DavidA