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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：
8292117
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 2013-12-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8292117
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 research and development research study sarkosyl success symposium tandem mass spectrometry tau Proteins tau aggregation

项目摘要

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.

tau病是一类神经退行性疾病，其特征是微管相关蛋白tau过度磷酸化引起的细胞内纤维聚集。这一神经退行性疾病家族包括阿尔茨海默病、皮质基底变性、进行性核上性麻痹、与17号染色体相关的帕金森病额颞叶痴呆（FTDP-17）和皮克病等。遗传学、生物化学和神经病理学研究表明，tau蛋白的生物学功能的破坏，无论是通过突变、过度磷酸化和/或异常的蛋白质相互作用，都可能在神经变性过程中发挥核心作用。然而，tau介导的神经退行性变的分子机制仍然知之甚少。JNPL3是一种转基因小鼠，表达携带突变（hTauP301L）的人类tau蛋白，通常在FTDP-17的亲缘关系中发现。JNPL3小鼠早在6个月大时就会出现tau聚集物积累后的行为和运动缺陷。与人类的情况一样，JNPL3小鼠的细胞内tau聚集体以年龄依赖性和脑区域特异性的方式形成。先前的研究是由首席研究员（PI）进行的，旨在鉴定身患绝症的JNPL3小鼠中的tau相关蛋白。从绝症JNPL3小鼠脑提取物中免疫沉淀Tau蛋白，并对免疫沉淀蛋白进行串联质谱分析。PI发现了一种具有钙结合活性的新型tau相关蛋白。这种关联在AD和FTDP-17的人类颞叶脑裂解液中得到证实。在这里，我们将这种新蛋白称为Tau-EF含手相关蛋白（TEA）。为了进一步了解Tau蛋白与TEA之间关联的生理和/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与tau蛋白关联的分子要求；(3)了解TEA蛋白在tau介导的神经退行性变中的作用。该新蛋白在JNPL3小鼠和人脑中的生理和病理作用及其与tau蛋白的关联的表征可能为人类tau病的分子机制提供相关信息。