Dual CHIP Functions Control Tau Triage In Alzheimer's Disease

双芯片功能控制阿尔茨海默氏病的 Tau 分类

• 批准号: 10319914
• 负责人: Todd Jonathan Cohen
• 金额: $ 61.97万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10319914
• 关键词: Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease patient; Animal Model; Behavioral; Binding; Biochemical; Biological Assay; Biophysics; Brain; Client; Clinical; Cognition; Cognitive deficits; Complex; Data; Disease; Disease Progression; Dissociation; Event; Genetic; Genetic study; Goals; Heat Shock 70kD Protein Binding Protein; Heat shock proteins; Heat-Shock Response; Human; Immunotherapy; Impaired cognition; Impairment; Individual; Light; Link; MAPT gene; Mediating; Mediator of activation protein; Microtubule Stabilization; Microtubules; Modeling; Modification; Molecular; Molecular Chaperones; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Onset of illness; Pathogenesis; Pathology; Patients; Play; Process; Property; Protein Dephosphorylation; Protein Microchips; Proteins; Quality Control; Regulation; Role; Site; Spinocerebellar Ataxias; Tauopathies; Testing; Therapeutic; Time; Triage; Ubiquitin; Variant; cognitive enhancement; cognitive function; factor C; in vitro Assay; in vivo; innovation; insight; mouse model; neuronal survival; neuroprotection; novel; pre-clinical; prevent; protective factors; protein expression; proteostasis; repaired; response; targeted treatment; tau Proteins; tau aggregation; tau expression; tau function; tau mutation; tau phosphorylation; therapeutic target; therapy development; ubiquitin ligase; ubiquitin-protein ligase

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.

项目概要/摘要 大脑中聚集的 tau 蛋白的积累是阿尔茨海默病 (AD) 的一个决定性特征，也是 预防 AD 进展的逻辑治疗目标。小鼠的遗传证据强烈支持这一观点： tau 蛋白会促进 AD 中的认知缺陷。虽然抗聚集和免疫治疗方法已经出现 作为减少大脑中 tau 蛋白聚集的潜在策略，这些药物针对的是晚期 tau 蛋白中间体。很多 对于在其他健康的神经元中引起 tau 蛋白聚集的早期事件知之甚少， 伴侣依赖性重折叠以补偿方式恢复 tau 功能的时间段 关键的微管 (MT) 稳定因子。我们寻求定义这些早期 tau 分类决策，因为 临床上非常希望在这个早期窗口期靶向 tau 蛋白，以防止 tau 蛋白积累，特别是在 无症状个体在疾病发作后数年至数十年。热休克 70 相互作用的 C 末端 蛋白质（或 CHIP）在协调蛋白质质量控​​制方面发挥着核心作用。虽然大多数先前的研究已经 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体， 现在的研究表明，CHIP 包含一种人们知之甚少的内在伴侣功能，该功能可发挥作用 完全独立于其 E3 连接酶活性。脊髓小脑共济失调 16 (SCAR 16) 的遗传学研究 患者，一种罕见的神经退行性疾病，表明仅 CHIP 共伴侣活性的丧失就足够了 导致神经退行性变和认知功能障碍。这些先前的研究与我们引人注目的新研究相结合 初步数据显示 CHIP 直接结合并陪伴 tau 以促进其去磷酸化， 为CHIP介导的tau蛋白分类新模型提供有力支持。我们假设 CHIP 可以防止 异常的 tau 修饰和聚集，恢复正常的 tau 功能和 MT 稳定性，以及 改善 AD 相关的认知能力下降。在 Aim-1 中，我们将剖析 CHIP 作为监管者的双重功能 使用体外生化和生物物理测定法观察 tau 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 物种的新机制见解。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。我们将测试以下要求 CHIP 共伴侣在维持 MT 完整性方面的活性，从而促进神经元的存活，这将 否则会发生退化。最后，在 Aim-3 中，我们将测试 CHIP 辅助伴侣的临床意义 在 AD 动物模型中恢复认知功能。总的来说，我们的建议很重要，因为它将 阐明决定 tau 最初如何处理和分类的早期事件。也是很有创意的 因为它是第一个强调 CHIP 与 tau 发病机制相关的双分子功能的研究 这种毁灭性疾病的进展。