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

• 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
• 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' 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

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），对于其没有任何治疗。 存在疾病改善疗法。Tau蛋白病表型显示了一系列病理学特征 和临床综合征。翻译后修饰（PTMs）促进了 菌株或构象组装，有助于tau蛋白病，这意味着需要了解如何新的 PTM有助于tau蛋白病风险。瓜氨酸蛋白（citR），由肽基精氨酸脱亚胺酶（PAD）诱导， 导致不可逆PTM，通过中和带正电荷的精氨酸改变蛋白质结构/功能 蛋白质中的残基。我们发现，异常的tau蛋白激活神经元中的PAD 4（蛋白PAD 4，基因 PAD 14）; tau是PAD 4的客户，并且在14个精氨酸残基处被瓜氨酸化，并且这些变化与 减少tau蛋白磷酸化; citR阻止关键表位的tau蛋白磷酸化并影响tau蛋白清除;和 citR在AD和tau蛋白病的动物模型中升高。我们的中心假设认为，增加的PAD 4- 诱导的Tau citR阻止高级纤维化，这减少了缠结形成，改变了tau代谢， 影响结构/功能，并减少播种活动。该模型的假设将在体内和体内进行测试。 通过神经元PADi 4过表达和条件性敲除小鼠体外，多种生化技术， 电生理学和行为学方法。我们将建立神经元PADi 4表达如何影响tau蛋白 神经病理改变目的1将促进我们对PADi 4功能获得/丧失的理解，以建立 citR tau生物学的基础以及对不同tau蛋白病模型中行为的影响。我们将建立 citR如何在细胞模型中调节tau生物化学和生物学。目标2将机械地确定如何 PAD 4诱导的citR tau改变tau清除、聚集、接种和微管结合。我们将建立 常见人类tau蛋白病中citR tau蛋白时空特征目标3将提供定性框架 和citR tau在常见人类tau蛋白病中的接种活性。拟议的工作提供了必要的 这不仅为更好地表征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 在tau发病过程中PAD 4功能丧失和获得的机制原因。总的来说，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。