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

基本信息

批准号：
10539271
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
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-03-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10539271
关键词：
Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease patient Animal Model Behavioral Binding Biochemical Biological Assay Biophysics Brain Client Clinical Cognition Cognitive deficits Complex Cytoplasm 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 Link MAPT gene Mediating Mediator 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 neuropathology 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-1 therapeutic target therapy development ubiquitin ligase ubiquitin-protein ligase

项目摘要

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.

项目摘要/摘要大脑中综合tau蛋白的积累是阿尔茨海默氏病（AD）和A的定义特征逻辑理论的目标是防止AD进展。小鼠的遗传证据强烈支持这样的观念 Tau促进了AD中的认知缺陷。抗聚集和免疫疗法的方法已经出现作为减少大脑中tau聚集的潜在策略，这些靶向后期tau中间体。很多关于在其他健康的神经元中引起tau骨料的早期事件的了解少，依赖链酮的重折叠的时间段以补偿方式恢复tau的功能临界微管（MT）稳定因子。我们试图定义这些早期的tau分诊决定在此较早的窗口中临床靶向tau非常需要防止tau积累，尤其是在从疾病发作数十年的无症状个体。热休克的C末端70相互作用蛋白质（或芯片）在编排蛋白质质量控制中起着核心作用。虽然大多数先前的研究都有指出CHIP的E3连接酶活动是客户基质降解的主要调解人，包括Tau，现在的研究表明，芯片包含一个固有的伴侣函数，其运作完全独立于其E3连接酶活性。脊椎子宫共济失调16的遗传研究（疤痕16）患者是一种罕见的神经退行性疾病，表明仅芯片副酮活动的丧失就足够了引起神经变性和认知功能障碍。这些先前的研究，加上我们引人注目的新初步数据表明芯片直接结合和伴侣tau以促进其去磷酸化，为芯片介导的Tau Triage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，以及改善与广告相关的认知下降。在AIM-1中，我们将剖析Chip的双重功能作为调节器在体外使用生化和生物物理测定法，tau功能和磷酸化。这些研究将提供关于芯片靶向和维修异常tau物种的新机械洞察力。在AIM-2中，我们将探索 CHIP在通过MT的稳定中介导神经保护中的新作用。我们将测试要求 ChIP共伴侣活性在维持MT完整性方面，从而促进神经元的生存否则会发生变性。最后，在AIM-3中，我们将测试CHIP副酮的临床意义在AD动物模型中恢复认知的功能。总体而言，我们的建议很重要，因为它将阐明了决定最初处理和分类的早期事件。这也是创新的因为它是第一个强调与tau发病机理和这种毁灭性疾病的进展。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Ubiquitin ligase STUB1 destabilizes IFNγ-receptor complex to suppress tumor IFNγ signaling.

DOI：
10.1038/s41467-022-29442-x
发表时间：
2022-04-08
期刊：
Nature communications
影响因子：
16.6
作者：
Apriamashvili G;Vredevoogd DW;Krijgsman O;Bleijerveld OB;Ligtenberg MA;de Bruijn B;Boshuizen J;Traets JJH;D'Empaire Altimari D;van Vliet A;Lin CP;Visser NL;Londino JD;Sanchez-Hodge R;Oswalt LE;Altinok S;Schisler JC;Altelaar M;Peeper DS
通讯作者：
Peeper DS