The tau code of Alzheimer's disease

描述(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阿尔茨海默病中，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。为了深入了解在AD中伴随tau病变形成的修饰，我们使用质谱学方法对从真实的疾病组织标本中分离出的tau聚集体进行了初步的结构分析。我们的结果显示，一种以前未被发现的tau修饰，即赖氨酸甲基化，与tau聚合体发生了相互作用。初步的甲基化特征涉及已知的介导tau泛素化和其他翻译后修饰的位点，表明甲基化是正常的tau修饰，并可能影响疾病中tau病变的形成。我们现在提出一个探索性的项目，验证甲基化作为tau的一种病理生理修饰，将其置于与从死后人类组织中分离的正常和聚集的tau相关的修饰特征的背景中，并初步了解其对tau聚集倾向和微管聚合活性的潜在影响。一旦达到这项研究中提出的里程碑，AD领域将获得必要的关键信息，以调查tau蛋白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死前评估的新的疾病相关表位。 与公共卫生相关：阿尔茨海默病是老年人的主要痴呆疾病。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。这个项目的结果将帮助我们理解为什么在疾病中形成tau聚集体，如何改进它们的死前检测，以及如何控制它们的形成。

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.