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）：阿尔茨海默氏病（AD）的一部分是由由微管相关蛋白tau组成的细胞内夹杂物的出现。以高度普遍的零星形式驱动tau聚集的机制尚未完全了解，但似乎涉及异常的翻译后修饰。为了深入了解AD中Tau病变形成的修饰，我们对使用质谱法分离的TAU聚集体进行了初步结构分析。我们的结果表明，先前未识别的TAU修饰，赖氨酸甲基化，与Tau聚集体相互育。初步的甲基化签名涉及介导tau泛素化和其他翻译后修饰的部位，这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。现在，我们提出了一个探索性项目，以验证甲基化为病理生理的TAU修饰，将其置于与现年验尸中的正常和聚集的TAU相关的修饰特征的背景下，并获得了对其对微管聚合的潜在影响的初步洞察力。在实现本研究中提出的里程碑后，AD领域将获得研究所需的关键信息，以研究TAU翻译后修饰之间的潜在交叉言论，以指导对tau蛋白作用的甲基转移酶和脱甲基酶的未来鉴定，并确定可能有助于与疾病相关的新型表位，从而有助于识别AD的预评估。 公共卫生相关性：阿尔茨海默氏病是老年人的主要痴呆疾病。它是由由微管相关蛋白tau的聚集体组成的细胞病变的部分定义的。该项目的结果将有助于我们理解为什么tau骨料在疾病中形成，如何改善其验尸以及如何控制其形成。