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The role of a novel tau-associated protein in neurodegeneration

一种新型 tau 相关蛋白在神经退行性变中的作用

基本信息

批准号：
8117084
负责人：
IRVING E VEGA
金额：
$ 25.4万
依托单位：
UNIVERSITY OF PUERTO RICO RIO PIEDRAS
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-01 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8117084
关键词：
Address Age-Months Alzheimer&apos s Disease Applications Grants Area Behavioral Binding Biochemical Biological Process Biology Brain Brain region CCL7 gene Calcium Calcium Binding Calcium ion Calcium-Binding Domain California Chromosomes, Human, Pair 17 Clinic Collaborations Competence Core Facility Data Detection Development Diagnosis Disclosure EF Hand Motifs EF-Hand Domain Equipment Event Experimental Designs FTD with parkinsonism Faculty Family Fellowship Filament Foundations Frontotemporal Dementia Funding Genetic Goals Grant Homeostasis Human Human Pathology Immunoprecipitation In Vitro Insecta Institution International Interview Journals Laboratories Laboratory Research Lead Legal patent Letters Link Los Angeles MAPT gene Mammals Manuscripts Mass Spectrum Analysis Mediating Mentors Molecular Mus Mutation Nerve Degeneration Neurodegenerative Disorders Neurons Organ Paper Parkinsonian Disorders Peer Review Pennsylvania Physiological Pick Disease of the Brain Piedra Play Positioning Attribute Postdoctoral Fellow Preparation Principal Investigator Process Productivity Progressive Supranuclear Palsy Proteins Publications Publishing Puerto Rico Research Research Personnel Research Proposals Role Scientist Sequence Analysis Services Specificity Staging Tauopathies Temporal Lobe Terminally Ill Time TimeLine Training Training Activity Transgenic Mice United States National Institutes of Health Universities Vermont Virginia Work age related base career corticobasal degeneration hyperphosphorylated tau information gathering insight kindred meetings member motor deficit mouse model normal aging novel overexpression professor programs public health relevance research and development research study sarkosyl success symposium tandem mass spectrometry tau Proteins tau aggregation

项目摘要

DESCRIPTION (provided by applicant): Tauopathies are a family of neurodegenerative disorders characterized by the intracellular aggregation of filaments derived from hyperphosphorylated microtubule-associated protein tau. This family of neurodegenerative disorders includes Alzheimer's disease, corticobasal degeneration, progressive supranuclear palsy, frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17) and Pick disease, among others. Genetics, biochemical and neuropathological studies suggest that disruption of the biological function of tau proteins, either by mutations, hyperphosphorylation and/or aberrant protein interactions, may play a central role in the process of neurodegeneration. However, the molecular mechanism underlying tau-mediated neurodegeneration is still poorly understood. The JNPL3 is a transgenic mouse that expresses a human tau protein bearing a mutation (hTauP301L) commonly found in kindred with FTDP-17. The JNPL3 mice also develop behavioral and motor deficits following the accumulation of tau aggregates as early as 6-months of age. As is the case in humans, intracellular tau aggregates in JNPL3 mice are formed in an age-dependent and brain-region specific manner. Previous studies, conducted by the principal investigator (PI), were directed toward the identification of tau-associated proteins in terminally ill JNPL3 mice. Tau proteins were immunoprecipitated from terminally ill JNPL3 mice brain extract and the immunoprecipitated proteins were subjected to tandem mass spectrometry analysis. The PI identified a novel tau-associated protein that possesses calcium-binding activity. This association was validated in human temporal brain lysate from AD and FTDP-17. Herein, we refer to this novel protein as Tau-EF hand containing Associated protein (TEA). In order to further understand the physiological and/or pathological role of the association between Tau and TEA the following three research objectives will be addressed: (1) To understand the physiological role of TEA proteins; (2) To elucidate the molecular requirements for the association between TEA and tau proteins; (3) To understand the role of TEA proteins in tau-mediated neurodegeneration. The characterization of the physiological and pathological role of this novel protein and its association with tau proteins in JNPL3 mice and human brain may provide relevant information about the molecular mechanism underlying human tauopathy. Public Health Relevance: Tauopathies are a group of neurodegenerative disorders characterized by the pathological aggregation of the microtubule-associated protein tau. The pathological events leading to the aggregation of tau proteins are still unclear. The proposed project intends to characterize the role that the novel tau-associated protein TEA plays in the development and/or progression of tau-mediated neurodegeneration.

描述（由申请人提供）：Tau病是一个神经退行性疾病家族，其特征在于源自过度磷酸化微管相关蛋白tau的细丝的细胞内聚集。该神经退行性疾病家族包括阿尔茨海默病、皮质基底节变性、进行性核上性麻痹、与17号染色体相关的额颞叶痴呆伴帕金森综合征（FTDP-17）和皮克病等。遗传学、生物化学和神经病理学研究表明，通过突变、过度磷酸化和/或异常蛋白质相互作用破坏tau蛋白的生物学功能，可能在神经变性过程中发挥核心作用。然而，tau蛋白介导的神经变性的分子机制仍然知之甚少。JNPL 3是一种转基因小鼠，其表达携带突变（hTauP 301 L）的人tau蛋白，该突变通常在FTDP-17的亲属中发现。JNPL 3小鼠在早至6个月大时tau聚集体积累后也出现行为和运动缺陷。与人类的情况一样，JNPL 3小鼠中的细胞内tau聚集体以年龄依赖性和脑区域特异性方式形成。由主要研究者（PI）进行的先前研究旨在鉴定终末期JNPL 3小鼠中的tau相关蛋白。Tau蛋白从终末期疾病JNPL 3小鼠脑提取物中免疫沉淀，并对免疫沉淀的蛋白进行串联质谱分析。PI鉴定了一种具有钙结合活性的新型tau相关蛋白。这种关联在来自AD和FTDP-17的人颞脑裂解物中得到验证。在本文中，我们将这种新的蛋白质称为Tau-EF手包含相关蛋白（TEA）。为了进一步了解Tau和TEA之间的关联的生理和/或病理作用，将解决以下三个研究目标：（1）了解TEA蛋白的生理作用;（2）阐明TEA和tau蛋白之间的关联的分子要求;（3）了解TEA蛋白在tau介导的神经变性中的作用。这种新蛋白的生理和病理作用及其与JNPL 3小鼠和人脑中tau蛋白的相关性的表征可能提供有关人类tau蛋白病的分子机制的相关信息。公共卫生相关性：tau蛋白病是一组以微管相关蛋白tau的病理性聚集为特征的神经退行性疾病。导致tau蛋白聚集的病理事件仍不清楚。拟议的项目旨在表征新的tau相关蛋白TEA在tau介导的神经变性的发展和/或进展中所起的作用。