The tau code of Alzheimer's disease

阿尔茨海默病的 tau 密码

• 批准号: 8399904
• 负责人: Jeff Kuret
• 金额: $ 24.26万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-15 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8399904
• 关键词: Acetylation; Adult; Affect; Affinity; Alzheimer' s Disease; Amino Acid Sequence; Appearance; Binding; Brain; Burial; Code; Data; Detection; Diagnosis; Disease; Elderly; Epitopes; Filament; Future; Gene Expression; Genes; Genetic Code; Goals; Histone Code; Histones; Human; Impaired cognition; In Vitro; Length; Lesion; Light; Lysine; Maps; Mass Spectrum Analysis; Mediating; Metabolism; Methods; Methylation; Methyltransferase; Microtubule Polymerization; Microtubules; Missense Mutation; Modification; Nerve Degeneration; Neurofibrillary Tangles; Pathogenesis; Pattern; Peptides; Phosphorylation; Positioning Attribute; Post-Translational Protein Processing; Protein Isoforms; Proteolysis; Radial; Relative (related person); Research; Site; Specimen; Tauopathies; Tissues; Toxic effect; aged; density; driving force; glycosylation; human tissue; improved; insight; methyl group; multicatalytic endopeptidase complex; novel; paired helical filament; protein protein interaction; tau Proteins; tau aggregation; tau function; tau phosphorylation

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is defined in part by the appearance of intracellular inclusions composed of the microtubule associated protein tau. The mechanisms that drive tau aggregation in the highly prevalent sporadic form of AD are not fully understood, but appear to involve abnormal post-translational modifications. To gain insight into the modifications that accompany tau lesion formation in AD, we conducted a preliminary structural analysis of tau aggregates isolated from authentic disease tissue specimens using mass spectrometry methods. Our results revealed that a previously unrecognized tau modification, lysine methylation, copurified with tau aggregates. The preliminary methylation signature involved sites that are known to mediate tau ubiquitylation and other post-translational modifications, suggesting that methylation is a normal tau modification and a candidate for influencing tau lesion formation in disease. We now propose an exploratory project to validate methylation as a pathophysiological tau modification, to place it into the context of modification signatures associated with both normal and aggregated tau isolated from post-mortem human tissue, and to gain preliminary insight into its potential effects on tau aggregation propensity an microtubule polymerization activity. Upon achieving the milestones proposed in this study, the AD field will gain the key information necessary to investigate potential cross-talk among tau post-translational modifications, to guide future identification of methyltransferases and demethylases that act on tau protein, and to identify novel disease-associated epitopes that may aid in the pre-mortem assessment of AD. PUBLIC HEALTH RELEVANCE: Alzheimer's disease is the leading dementing illness of the elderly. It is defined in part by the appearance of cellular lesions composed of aggregates of the microtubule-associated protein tau. Results from this project will help us understand why tau aggregates form in disease, how their pre-mortem detection may be improved, and how their formation may be controlled.

描述（由申请人提供）：阿尔茨海默病（AD）的部分定义是由微管相关蛋白 tau 组成的细胞内包涵体的出现。在高度流行的散发性 AD 中驱动 tau 蛋白聚集的机制尚不完全清楚，但似乎涉及异常的翻译后修饰。为了深入了解 AD 中 tau 病变形成所伴随的修饰，我们使用质谱方法对从真实疾病组织标本中分离出的 tau 聚集体进行了初步结构分析。我们的结果表明，以前未被识别的 tau 修饰（赖氨酸甲基化）与 tau 聚集体共纯化。初步的甲基化特征涉及已知介导 tau 泛素化和其他翻译后修饰的位点，表明甲基化是一种正常的 tau 修饰，并且是影响疾病中 tau 病变形成的候选者。我们现在提出了一个探索性项目，以验证甲基化作为一种​​病理生理学 tau 修饰，将其置于与从死后人体组织中分离出的正常和聚集 tau 相关的修饰特征中，并初步了解其对 tau 聚集倾向和微管聚合活性的潜在影响。在实现本研究中提出的里程碑后，AD 领域将获得必要的关键信息，以调查 tau 翻译后修饰之间的潜在串扰，指导未来识别作用于 tau 蛋白的甲基转移酶和去甲基酶，并识别可能有助于 AD 死前评估的新疾病相关表位。 公共卫生相关性：阿尔茨海默病是老年人的主要痴呆症。它的部分定义是由微管相关蛋白 tau 聚集体组成的细胞损伤的出现。该项目的结果将帮助我们了解为什么 tau 蛋白聚集体在疾病中形成、如何改进其死前检测以及如何控制其形成。