Tau Homeostasis and Neurodegeneration

描述(申请人提供)：阿尔茨海默病大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原纤维缠结。虽然到目前为止大多数研究都集中在tau缠结的合成上，但我们假设tau的积累是由于细胞蛋白质降解机制的故障造成的。蛋白质降解远不是一种被动的现象，它需要大量的能量消耗，并以非常高的特异性进行调节，以清除细胞中的有毒蛋白质。我们的假说得到了其他神经退行性疾病的支持，如脊髓小脑退行性变，在这些疾病中，新出现的证据表明，蛋白质降解途径在疾病病理中发挥关键作用，就像它们在细胞内稳态中具有核心重要性一样。然而，这些降解性缺陷的机制及其在疾病级联中的作用尚不清楚。需要对神经纤维病理学的这一方面进行深入的检查。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tau的产生、降解和神经元中的缠结形成。2)确定tau的产生、降解和缠结形成是否在神经元中诱导应激反应通路。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，因为目前还没有在神经元中进行这些测量的技术。4)开发一个全面的tau细胞途径的机制模型，整合所有这些相互竞争的细胞过程。对tau路径进行计算模拟和敏感性分析，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动态平衡的生化和细胞途径，重点关注降解途径、缠结形成和导致细胞凋亡的长期应激反应。确定tau通路中作为治疗干预良好靶点的步骤。

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.