Tau Homeostasis and Neurodegeneration

Tau 蛋白稳态和神经退行性变

• 批准号: 7408793
• 负责人: ANNE SKAJA ROBINSON
• 金额: $ 5.67万
• 依托单位: UNIVERSITY OF CALIFORNIA SANTA BARBARA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-10-01 至 2008-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7408793
• 关键词: Affect; Alzheimer' s Disease; Amyloid; Amyloid Proteins; Animals; Apoptosis; Axon; Biochemical; Brain; Categories; Cell physiology; Cells; Class; Collaborations; Computer Simulation; Condition; Defect; Degradation Pathway; Depth; Disease; Energy Metabolism; Enzymes; Failure; Frontotemporal Dementia; Goals; Homeostasis; Indium; Knowledge; Left; Link; Measurement; Measures; Microtubule-Associated Proteins; Modeling; Molecular Chaperones; Nerve Degeneration; Neurofibrillary Tangles; Neurons; Pathology; Pathway interactions; Phosphorylation; Phosphotransferases; Play; Production; Protein Dephosphorylation; Proteins; Research; Role; Senile Plaques; Site; Solubility; Specificity; Spinocerebellar Degenerations; Technology; Therapeutic Intervention; Toxic effect; Ubiquitination; Yeasts; biological adaptation to stress; extracellular; inorganic phosphate; neurofibrillary tangle formation; protein degradation; tau Proteins; tau aggregation; tau dysfunction; tau phosphorylation

DESCRIPTION (provided by applicant): Alzheimer brain shows two types of insoluble material: the extracellular amyloid protein and the intracellular neurofibrillary tangles formed from tau protein. Although most studies to date have focused on tau tangle synthesis, we hypothesize that tau accumulation results from failures in the cellular protein degradation machinery. Far from being a passive phenomenon, protein degradation requires a significant expenditure of energy, and is regulated with a very high degree of specificity to rid the cell of toxic proteins. Support for our hypothesis comes from other neurodegenerative conditions such as spinocerebellar degeneration, in which emerging evidence suggests that protein degradation pathways play key roles in disease pathologies, just as they are of central importance in cell homeostasis. However, the mechanisms of these degradative defects, and their roles in the disease cascade are unknown. An in-depth examination of this facet of neurofibrillary pathology is required. Specific aims: 1) Determine how changes in the levels of chaperone proteins (such as BiP) involved in the stress response affect tau production, degradation, and tangle formation in neurons. 2) Determine whether tau production, degradation, and tangle formation induces stress response pathways in neurons. 3) Measure how phosphorylation (and dephosphorylation) of tau affects its production, degradation, and tangle formation. This study may need to be carried out in yeast, as the technology to perform these measurements in neurons is not yet available. 4) Develop a comprehensive mechanistic model of tau cellular pathways, integrating all of these competing cellular processes. Perform a computational simulation and a sensitivity analysis of the tau pathways to identify the keys steps in tau tangle formation. The long-term goals of our overall project and new collaboration are to: Define biochemical and cellular pathways of tau homeostasis, focusing on degradation pathways, tangle formation, and long-term stress response leading to apoptosis. Identify steps in the tau pathways that are good targets for therapeutic intervention.

描述（由申请人提供）：阿尔茨海默氏症脑显示两种类型的不溶性物质：细胞外淀粉样蛋白和由tau蛋白形成的细胞内神经元缠结。尽管迄今为止大多数研究都集中在tau缠结合成上，但我们假设tau积累是由于细胞蛋白质降解机制的失败。蛋白质降解远非一种被动现象，它需要大量的能量消耗，并且以非常高的特异性进行调节，以清除细胞中的有毒蛋白质。支持我们的假设来自其他神经退行性疾病，如脊髓小脑变性，其中新出现的证据表明，蛋白质降解途径在疾病病理学中起着关键作用，就像它们在细胞内稳态中具有核心重要性一样。然而，这些降解缺陷的机制及其在疾病级联中的作用尚不清楚。需要对神经病理学的这一方面进行深入的研究。具体目标：1）确定参与应激反应的伴侣蛋白（如BiP）水平的变化如何影响神经元中tau蛋白的产生、降解和缠结形成。2)确定tau蛋白的产生、降解和缠结的形成是否会诱导神经元的应激反应途径。3)测量tau的磷酸化（和去磷酸化）如何影响其产生，降解和缠结形成。这项研究可能需要在酵母中进行，因为在神经元中进行这些测量的技术还没有。4)开发tau细胞通路的综合机制模型，整合所有这些竞争性细胞过程。对tau通路进行计算机模拟和敏感性分析，以确定tau缠结形成的关键步骤。我们整个项目和新合作的长期目标是：定义tau稳态的生化和细胞途径，重点是降解途径，缠结形成和导致细胞凋亡的长期应激反应。 确定tau通路中的步骤，这些步骤是治疗干预的良好靶点。

项目成果

Vulnerabilities in the tau network and the role of ultrasensitive points in tau pathophysiology.

tau 网络的脆弱性以及超敏感点在 tau 病理生理学中的作用。

• DOI: 10.1371/journal.pcbi.1000997
• 发表时间: 2010
• 期刊: PLoS computational biology
• 影响因子: 4.3
• 作者: Yuraszeck,TheresaM;Neveu,Pierre;Rodriguez-Fernandez,Maria;Robinson,Anne;Kosik,KennethS;Doyle3rd,FrancisJ
• 通讯作者: Doyle3rd,FrancisJ