Dual CHIP Functions Control Tau Triage In Alzheimer's Disease

项目总结/摘要 聚集的tau蛋白在脑中的积累是阿尔茨海默病（AD）的定义特征，并且是阿尔茨海默病（AD）的一个特征。 预防AD进展的合理治疗目标。小鼠的遗传学证据有力地支持了这一观点， tau促进AD中的认知缺陷。虽然抗聚集和免疫治疗方法已经出现， 作为减少脑中tau聚集的潜在策略，这些靶向晚期tau中间体。多 关于在其他健康神经元中引起tau聚集的早期事件， 一段时间，其中伴侣依赖性重折叠以补偿方式起作用以恢复tau功能， 一个关键的微管（MT）稳定因子。我们试图定义这些早期的tau分流决定，因为 在该较早窗口中临床靶向tau是非常期望的，以防止tau积累，特别是在 无症状的个体从疾病发作起数年至数十年。热休克70的C末端-相互作用 蛋白质（或CHIP）在协调蛋白质质量控制中起着核心作用。虽然大多数先前的研究 指出CHIP的E3连接酶活性是包括tau在内的客户底物降解的主要介质， 现在的研究表明，CHIP含有一种知之甚少的内在伴侣功能， 完全独立于其E3连接酶活性。脊髓小脑性共济失调16（SCAR 16）的遗传学研究 患者，一种罕见的神经退行性疾病，表明单独丧失CHIP共伴侣活性就足够了， 导致神经退化和认知功能障碍这些先前的研究，结合我们引人注目的新研究， 初步数据显示CHIP直接结合和陪伴tau蛋白以促进其去磷酸化， 为CHIP介导的tau分类的新模型提供强有力的支持。我们假设芯片可以防止 异常的tau修饰和聚集，恢复正常的tau功能和MT稳定，和 改善AD相关的认知能力下降。在Aim-1中，我们将剖析CHIP作为以下调节器的双重功能： 使用生物化学和生物物理学测定在体外研究tau蛋白的功能和磷酸化。这些研究将提供 关于CHIP如何靶向和修复异常tau种类的新机制见解。在Aim-2中，我们将探索 CHIP通过稳定MT介导神经保护的新作用。我们将测试的要求， CHIP共伴侣蛋白在维持MT完整性中的活性，从而促进神经元的存活， 否则就会退化。最后，在Aim-3中，我们将测试CHIP共伴侣的临床意义 在AD动物模型中恢复认知的功能。总的来说，我们的建议是重要的，因为它将 阐明决定tau最初如何处理和分类的早期事件。也是创新 因为它是第一个强调与tau发病机制相关的CHIP的双重分子功能， 这种毁灭性疾病的发展

PROJECT SUMMARY/ABSTRACT The accumulation of aggregated tau protein in the brain is a defining feature of Alzheimer’s disease (AD) and a logical therapeutic target to prevent AD progression. Genetic evidence in mice strongly supports the notion that tau promotes cognitive deficits in AD. While anti-aggregation and immunotherapy approaches have emerged as potential strategies to reduce tau aggregation in the brain, these target late-stage tau intermediates. Much less is known about the early-stage events that give rise to tau aggregates in otherwise healthy neurons, a time period in which chaperone-dependent refolding acts in a compensatory manner to restore tau function as a critical microtubule (MT) stabilizing factor. We seek to define these early-stage tau triage decisions since clinically targeting tau in this earlier window is highly desirable to prevent tau accumulation, particularly in asymptomatic individuals years to decades from disease onset. The C-terminus of heat shock 70-interacting protein (or CHIP) plays a central role in orchestrating protein quality control. While most prior studies have pointed to CHIP’s E3 ligase activity as a principal mediator of client substrate degradation including tau, studies now indicate that CHIP contains a poorly understood intrinsic chaperone function that operates completely independent of its E3 ligase activity. Genetic studies of spinocerebellar ataxia 16 (SCAR 16) patients, a rare neurodegenerative disorder, showed that loss of CHIP co-chaperone activity alone is sufficient to cause neurodegeneration and cognitive dysfunction. These prior studies, combined with our compelling new preliminary data showing that CHIP directly binds and chaperones tau to facilitate its dephosphorylation, provide strong support for a new model of CHIP-mediated tau triage. We hypothesize that CHIP prevents aberrant tau modifications and aggregation, restores normal tau function and MT stabilization, and ameliorates AD-related cognitive decline. In Aim-1, we will dissect CHIP’s dual functions as a regulator of tau function and phosphorylation using biochemical and biophysical assays in vitro. These studies will provide new mechanistic insights into how CHIP targets and repairs abnormal tau species. In Aim-2, we will explore a novel role for CHIP in mediating neuroprotection via the stabilization of MTs. We will test the requirements for CHIP co-chaperone activity in maintaining MT integrity and hence promoting survival in neurons that would otherwise undergo degeneration. Finally, in Aim-3, we will test the clinical implications of CHIP co-chaperone function in restoring cognition in an animal model of AD. Overall, our proposal is significant because it will illuminate the early-stage events that determine how tau is initially processed and triaged. It is also innovative because it is the first to highlight dual molecular functions of CHIP that are relevant to tau pathogenesis and the progression of this devastating disease.