Emerging Role of Tau Citrullination During Alzheimer’s disease and Tauopathies

Tau 瓜氨酸化在阿尔茨海默病和 Tau 病中的新作用

基本信息

批准号：
10231514
负责人：
Daniel Carl Lee
金额：
$ 167.28万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10231514
关键词：
Affect Age Aging Alzheimer&apos s Disease Amino Acid Substitution Animal Model Animals Area Arginine Arginine deiminase Behavior Behavioral Binding Biochemical Biochemistry Biology Biosensor Cell model Cells Charge Client Clinical Cognition Disease Electrophysiology (science)Epitopes Fostering Foundations Genes Goals Human Impaired cognition In Vitro Knock-out Knockout Mice Knowledge Lead Long-Term Potentiation Metabolism Microdialysis Microtubule Polymerization Microtubules Modeling Molecular Conformation Molecular Target Mus Nerve Degeneration Neurodegenerative Disorders Neurofibrillary Tangles Neurons Pathogenesis Pathologic Pathology Pathway interactions Phenotype Phosphorylation Play Post-Translational Protein Processing Proteins Research Risk Role Site Structure Syndrome Tauopathies Techniques Testing Therapeutic Tissues Tubulin Work age related cell type conditional knockout conformer dimer extracellular gain of function improved in vivo in vivo evaluation loss of function monomer nervous system disorder neurofibrillary tangle formation neuropathology normal aging novel overexpression polymerization prevent protein structure function spatiotemporal tau Proteins tau aggregation tau function tau phosphorylation

项目摘要

Emerging Role of Tau Citrullination During Alzheimer’s disease and Tauopathies Human tauopathies are a group of neurological disorders, including Alzheimer’s disease (AD), for which no disease modifying therapies exist. Tau proteinopathic phenotypes show a spectrum of pathological hallmarks and clinical syndromes. There is increasing recognition that post-translational modifications (PTMs) promote strain or conformational assemblies that contribute to tauopathies, signifying a need to understand how novel PTMs contribute to tauopathy risk. Protein citrullination (citR), induced by peptidyl arginine deiminases (PADs), leads to an irreversible PTM that alters protein structure/ function by neutralizing positively charged arginine residues within proteins. We discovered that aberrant tau activates PAD4 in neurons (protein PAD4, gene PADi4); tau is client of PAD4 and is citrullinated at 14 arginine residues and those changes are associated with reduced tau fibrillization; citR prevents tau phosphorylation of key epitopes and impacts tau clearance; and tau citR is elevated in AD and in animal models of tauopathy. Our central hypothesis argues that increased PAD4- induced tau citR prevents higher-order fibrillization, which decreases tangle formation, alters tau metabolism, impacts structure/ function, and reduces seeding activity. Assumptions of this model will be tested in vivo and in vitro by neuronal PADi4 overexpression and conditional knockout mice, multiple biochemical techniques, electrophysiologic, and behavioral approaches. We will establish how neuronal PADi4 expression impacts tau neuropathologic changes. Aim 1 will advance our understanding for PADi4 gain/ loss of function to establish the foundation for citR tau biology and the impact on behavior in different models of tauopathy. We will establish how citR regulates tau biochemistry and biology in cellular models. Aim 2 will mechanistically determine how PAD4-induced citR tau alters tau clearance, aggregation, seeding and microtubule binding. We will establish the spatio-temporal signature of citR tau in common human tauopathies. Aim 3 will provide the qualitative framework and seeding activity of citR tau in common human tauopathies. The proposed work provides the necessary foundation in not only better characterizing the role of citR in tauopathies, but also further establishing the first mechanistic cause for loss and gain of function of PAD4 during tau pathogenesis. Overall, our application describes a new tau PTM and provide a therapeutic strategy for a new pathway in tau biology and in AD.

Tau 瓜氨酸化在阿尔茨海默病和 Tau 病中的新作用人类 tau蛋白病是一组神经系统疾病，包括阿尔茨海默病 (AD)，目前尚无治疗方法存在疾病修饰疗法。Tau 蛋白病表型显示出一系列病理特征。人们越来越认识到翻译后修饰（PTM）会促进疾病的发生。导致tau蛋白病的应变或构象组装，意味着需要了解其新颖性 PTM 会导致由肽基精氨酸脱亚胺酶 (PAD) 诱导的蛋白质瓜氨酸化 (citR) 风险。导致不可逆的 PTM，通过中和带正电荷的精氨酸来改变蛋白质结构/功能我们发现异常的 tau 蛋白会激活神经元中的 PAD4（蛋白 PAD4，基因）。 PADi4)；tau 是 PAD4 的客户，在 14 个精氨酸残基处被瓜氨酸化，这些变化与减少 tau 纤维化；citR 防止关键表位的 tau 磷酸化并影响 tau 清除； citR 在 AD 和 tau 蛋白病动物模型中升高，我们的中心假设认为 PAD4- 升高。诱导的 tau citR 可防止高阶纤维化，从而减少缠结形成，改变 tau 代谢，影响结构/功能，减少和播种活性，该模型的假设将在体内和体内进行测试。体外通过神经PADi4过表达和条件敲除小鼠，多种生化技术，我们将确定神经 PADi4 表达如何影响 tau。目标 1 将增进我们对 PADi4 功能获得/丧失的理解，以建立我们将建立 citR tau 生物学基础以及对不同 tau 病模型行为的影响。 citR 如何在细胞模型中调节 tau 生物化学和生物学，Aim 2 将机械地决定如何调节。 PAD4 诱导的 citR tau 改变 tau 清除、聚集、播种和微管结合。常见人类 tau 病中 citR tau 的时空特征将提供定性框架。以及 citR tau 在常见人类 tau 病中的播种活性。不仅为更好地表征 citR 在 tau蛋白病中的作用奠定了基础，而且还进一步建立了第一个 tau 发病机制中 PAD4 功能丧失和获得的机制原因总体而言，我们的应用。描述了一种新的 tau PTM，并为 tau 生物学和 AD 中的新途径提供了治疗策略。