Posttranslational processing of tau: function & dysfunction

tau 的翻译后加工：功能

基本信息

批准号：
7626428
负责人：
Gail V. W. Johnson
金额：
$ 27.01万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-06-01 至 2012-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7626428
关键词：
Address Affect Alzheimer&apos s Disease Amino Acids Antibodies Attenuated Binding Biological Models Brain C-terminal Caspase Caspase-1 Cell Death Cell Death Process Cell Survival Cells Cessation of life Chinese Hamster Ovary Cell Cleaved cell Client Complex Cytoskeleton Data Development Disease Event Functional disorder Glycogen Synthase Kinase 3 Glycogen Synthase Kinases Goals Heat shock proteins Heat-Shock Response In Vitro Knockout Mice Lead Length Mediating Membrane Microtubule-Associated Proteins Microtubules Modeling Molecular Molecular Chaperones Molecular Conformation Mus Mutate Nature Neurites Neurodegenerative Disorders Neurofibrillary Tangles Neuroglia Neuronal Dysfunction Neurons Outcome Oxidative Stress PC12 Cells Pathogenesis Pathologic Pathologic Processes Phosphorylation Phosphorylation Site Physiological Play Principal Investigator Process Property Protein Isoforms Proteins Quality Control RNA Interference Recruitment Activity Research Personnel Resistance Role Scaffolding Protein Series Signal Pathway Signaling Protein Site Solubility Staining method Stains Structure System Testing Tetracyclines Therapeutic Toxic effect Ubiquitin Ubiquitin-Conjugating Enzymes Ubiquitination Viral Vector aberrant posttranslational tau processing caspase-2 follow-up gain of function loss of function multicatalytic endopeptidase complex mutant neuron loss neuronal survival programs protein aggregate research study sarkosyl stressor tau Proteins tau aggregation tau conformation tau dysfunction tau function tau interaction tau mutation tau phosphorylation tau-1 tau-microtubule interaction therapeutic target ubiquitin-protein ligase vector

项目摘要

DESCRIPTION (provided by applicant): Tau is a microtubule-associated protein that plays a pivotal role in the pathogenesis of Alzheimer's disease (AD). Site-specific phosphorylation regulates tau function and in AD brain tau is abnormally phosphorylated, is functionally impaired, is abnormally cleaved and accumulates as filamentous structures, events that likely impair neuronal function. Although it is clear that all these changes in tau take place in AD brain, the sequence of events and their contribution to neuronal cell death in Alzheimer's disease has not been clearly delineated. Our long range goal is to fully elucidate the sequence of pathological processes that result in aberrant posttranslational processing of tau and how these events compromise neuronal survival in AD brain so that effective therapeutics can be developed. The objective of this project is to determine how the phosphorylation of specific sites on tau affect tau-microtubule interactions, tau oligomerization, tau interaction with molecular chaperones (and thus its functional state), and tau turnover through the ubiquitin-proteasome system. The central hypothesis of this application is that a cascade of tau phosphorylation events in which glycogen synthase kinase 3 (GSK3) plays a key role, initially results in impaired microtubule binding and subsequently, in conjunction with caspase-cleavage, results in tau aggregation. These processes disrupt the ability of chaperones to regulate tau function and turnover and ultimately result in increased cellular toxicity. The rationale for these studies is that once it is known how specific posttranslational processes negatively impact tau function and contribute to neuronal dysfunction and death, then therapeutic targets for the treatment of Alzheimer's disease can be identified. The objectives of this project will be accomplished through three Specific Aims that test the hypotheses: (1) that phosphorylation of key sites on tau impairs tau function, increases tau-tau interactions and plays a central role in tau's facilitation of cell death processes, (2) that caspase cleavage of tau increases its propensity to self-associate and decrease cell survival, and that these effects are exacerbated by phosphorylation of specific sites on tau, and (3) that chaperones and the E3 ubiquitin ligase CHIP control tau conformation and proteasome targeting, that these interactions are regulated by site-specific tau phosphorylation and that tau cleaved by caspases accumulates because it is no longer an efficient substrate of the proteasome system. Overall these are important and timely studies that will clearly define the role of site-specific phosphorylation, caspase cleavage and the impact of chaperones and the ubiquitin-proteasome system on pathological changes in tau that contribute to the disease processes in Alzheimer's disease.

描述（由申请人提供）：TAU是一种微管相关蛋白，在阿尔茨海默氏病（AD）的发病机理中起关键作用。位点特异性的磷酸化调节tau功能，并且在AD脑中，tau异常磷酸化，功能受损，异常裂解并积聚为丝状结构，可能会损害神经元功能的事件。尽管很明显，tau的所有这些变化都在AD大脑中发生，但事件的序列及其对阿尔茨海默氏病中神经元细胞死亡的贡献尚未清楚地描述。我们的远距离目标是充分阐明导致TAU的异常翻译后处理的病理过程序列，以及这些事件如何损害AD大脑中的神经元存活，从而可以开发有效的治疗剂。该项目的目的是确定特定位点在tau上的磷酸化如何影响tau-Microubule相互作用，Tau低聚，Tau与分子伴侣（及其功能状态）的相互作用以及通过泛素蛋白蛋白酶体系统的tau转换。该应用的中心假设是一系列tau磷酸化事件，其中糖原合酶激酶3（GSK3）起着关键作用，最初导致微管结合受损，随后与caspase-cleavage结合，导致TAU聚集。这些过程破坏了伴侣调节tau功能和周转的能力，并最终导致细胞毒性增加。这些研究的理由是，一旦知道特定的翻译后过程如何对tau功能产生负面影响并导致神经元功能障碍和死亡，那么可以确定治疗阿尔茨海默氏病的治疗靶标。 The objectives of this project will be accomplished through three Specific Aims that test the hypotheses: (1) that phosphorylation of key sites on tau impairs tau function, increases tau-tau interactions and plays a central role in tau's facilitation of cell death processes, (2) that caspase cleavage of tau increases its propensity to self-associate and decrease cell survival, and that these effects are exacerbated by tau上特定位点的磷酸化以及（3）伴侣和E3泛素连接酶芯片对照tau构象和蛋白酶体靶向的磷酸化，这些相互作用是由位点特异性的tau磷酸化调节的，而caspass裂解的tau会积累，因为它已经不再是蛋白酶蛋白酶体的有效的蛋白酶系统。总体而言，这些都是重要且及时的研究，它将清楚地定义特定地点的磷酸化，caspase裂解以及伴侣伴侣的影响以及泛素蛋白蛋白酶体对TAU病理变化的影响，这会导致阿尔茨海默氏病疾病过程。