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Biochemical and in vivo determinants of tau neurotoxicity

tau 神经毒性的生化和体内决定因素

基本信息

批准号：
8885932
负责人：
MEL B FEANY
金额：
$ 45.99万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-28 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8885932
关键词：
Affect Alzheimer&apos s Disease Alzheimer&apos s disease model Amino Acids Amyloid beta-Protein Precursor Animal Model Asses Binding Biochemical Biochemistry Biological Biological Models Brain Cell Culture Techniques Cells Cessation of life Chromosomes, Human, Pair 17 Data Deposition Diamond Disease Drosophila genus FTD with parkinsonism Frontotemporal Dementia Gene Transfer Techniques Generations Genes Genetic Health Human In Vitro Inclusion Bodies Influentials Laboratories Lesion Link Mediating Mediator of activation protein Memory impairment Methods Microtubule Stabilization Microtubules Missense Mutation Modeling Molecular Mus Mutation Nerve Degeneration Neurodegenerative Disorders Neurofibrillary Tangles Neurons Parkinsonian Disorders Pathogenesis Pathogenicity Pathologic Production Progressive Supranuclear Palsy Property Protein Isoforms Publishing RNA Splicing Reporting Resources Senile Plaques System Tauopathies Testing Time Toxic effect Transgenic Mice Transgenic Organisms Variant Work age related corticobasal degeneration density design experience extracellular human disease in vivo mouse model mutant neurotoxic neurotoxicity progressive neurodegeneration protein aggregate research study synuclein tau Proteins tau aggregation tau microtubule binding domain tau mutation tau phosphorylation tool

项目摘要

DESCRIPTION (provided by applicant): Alzheimer's disease is the most common neurodegenerative disorder and is characterized pathologically by the intraneuronal deposition of abnormally phosphorylated and aggregated tau protein and by the formation of extracellular amyloid plaques. Abnormal deposition of tau into neurofibrillary tangles is also the primary pathologic feature of a group of less common disorders, collectively termed the "tauopathies." To define the molecular mechanisms controlling tau-induced neurodegeneration we (Dr. Gamblin) have performed extensive biochemical characterization of tau variants, including splicing isoforms and mutants linked to the familial tauopathy frontotemporal dementia and parkinsonism linked to chromosome 17. Importantly, these biochemical studies have defined tau variants with altered aggregation and microtubule binding properties. In parallel we (Dr. Feany) have created Drosophila models of tauopathy. Our models recapitulate key features of the human diseases, including age-dependent neurodegeneration, abnormal tau phosphorylation, aggregation of tau into fibrillary tangle-like inclusions, and early death. We will now combine our strengths in biochemistry and in vivo tauopathy modeling to define the species of tau that cause cellular and organismal toxicity in tauopathies.

描述（由申请人提供）：阿尔茨海默氏病是最常见的神经退行性疾病，其病理学特征在于神经元内异常磷酸化和聚集的tau蛋白沉积以及细胞外淀粉样斑块的形成。 tau蛋白异常沉积到神经原纤维缠结中也是一组不太常见的疾病的主要病理特征，统称为“tau蛋白病”。为了确定控制 tau 诱导的神经变性的分子机制，我们（Gamblin 博士）对 tau 变体进行了广泛的生化表征，包括与家族性 tau 病额颞叶痴呆和与 17 号染色体相关的帕金森病相关的剪接异构体和突变体。重要的是，这些生化研究已经定义了具有改变的聚集和分布的 tau 变体。微管结合特性。与此同时，我们（Feany 博士）创建了 tau 蛋白病的果蝇模型。我们的模型概括了人类疾病的关键特征，包括年龄依赖性神经变性、tau 蛋白磷酸化异常、tau 蛋白聚集成纤维缠结状包涵体以及过早死亡。我们现在将结合我们的生物化学和体内 tau 蛋白病模型的优势，可定义在 tau 蛋白病中引起细胞和有机体毒性的 tau 蛋白种类。