Autophagic Clearance of Aberrant Tau: Biochemical and Therapeutic Implications

异常 Tau 蛋白的自噬清除：生化和治疗意义

基本信息

批准号：
8841415
负责人：
Karen Duff
金额：
$ 42.11万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-01 至 2017-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8841415
关键词：
Address Animal Model Attenuated Autophagocytosis Autophagosome Axon Axonal Transport Biochemical Cell Death Cell model Cells Degradation Pathway Development Disease Disease Progression Drug Targeting Enhancers Equilibrium Event Excision Failure Functional disorder Genetic Health Human In Vitro Label Libraries Lysosomes Microfluidics Molecular Bank Molecular Chaperones Mus Neurodegenerative Disorders Neurofibrillary Tangles Neurons Organelles Outcome Measure Pathology Pathway interactions Patients Pharmaceutical Preparations Phenotype Play Proteins Quality Control Reporter Role Staging System Tauopathies Testing Therapeutic Therapeutic Intervention Tissues Transgenes Ubiquitin United States National Institutes of Health Vacuole Vesicle alpha synuclein chemical genetics drug candidate end stage disease human Huntingtin protein human tissue hyperphosphorylated tau in vivo insight mouse model multicatalytic endopeptidase complex novel protein aggregate protein misfolding tau Proteins tau aggregation tau mutation trafficking

项目摘要

DESCRIPTION (provided by applicant): Intracellular inclusions of misfolded proteins are the hallmark of many neurodegenerative diseases. Dysfunction of either of the two proteolytic pathways involved in clearing abnormal or obsolete cellular proteins, the ubiquitin-proteasome system (UPS) and the autophagic-lysosomal system (A-LS) may underlie the development of the disease. Macroautophagy (autophagy), a major degradative pathway of the lysosomal system, plays a significant role in the removal of organelles and protein aggregates that are too large, or that cannot be unfolded by chaperone proteins and that are consequently unable to be degraded by the UPS. An equilibrium exists between autophagosome formation and clearance by lysosomes, and uncompromised vesicular trafficking, heterotypic organelle fusion and lysosomal function are critical for the terminal stages of autophagosomal degradation. The A-LS has been shown to play an important role in the clearance of misfolded, aggregate-prone proteins such as α-synuclein and huntingtin. In general, we hypothesize that the UPS is upregulated to clear misfolded tau species early during the disease, but the system becomes overwhelmed as larger aggregates of tau accumulate. We envisage that the A-LS is then upregulated in an effort to compensate for the lost UPS activity and to clear the aggregates but ultimately both systems fail resulting in accelerated pathology and decline. The relationship between the accumulation of tau, the interplay between the UPS and A-LS, and the effect of relevant pharmacologic manipulations on outcome measures of relevance to human tauopathy will be assessed in three specific aims. Aim 1 will examine the interplay between the UPS, AL-S and tau accumulation in human tissue from patients with 4R tauopathies and will compare to two mouse models of 4R tauopathy that have been modified to express an autophagic marker. The mouse models will allow us to manipulate components of the autophagic pathways to further study the interplay with the UPS, with specific examination of what happens to specific ubiquitinated forms of proteins to confirm the significance of autophagic sufficiency in tauopathy progression in vivo. Aim 2 will use primary neurons from the aforementioned animal models to test the impact of dysfunction in a particular pathway (abnormal transport of autophagic vacuoles leading to failure of autophagic flux) and its impact on tauopathy, and whether compounds that activate A-LS or reduce the levels of hyperphosphorylated tau ameliorate the pathological phenotype. Aim 3 will identify if compounds identified by NCGC/NIH (National Chemical and Genetic Center) using the MLPCN (Molecular Library Probes Center Network) to reduce huntingtin aggregates and cell death are viable autophagic enhancers that can be used to treat tauopathy. Cumulatively, these studies will add insight into the relationship between clearance pathways, how and when they fail, and the impact of drugs that target autophagy as a therapeutic intervention for the tauopathies

描述（由适用提供）：错误折叠蛋白的细胞内夹杂物是许多神经退行性疾病的标志。涉及清除异常或过时的细胞蛋白，泛素蛋白 - 蛋白酶体系统（UPS）和自噬溶质体系统（A-LS）的两种蛋白水解途径中的功能障碍可能是该疾病发展的基础。大量噬菌体（自噬）是溶酶体系统的主要降解途径，在去除太大的细胞器和蛋白质聚集体中起着重要作用，或者不能被链酮蛋白且因此无法被UPS降解。自噬体的形成与溶酶体清除之间存在等效，以及副囊泡贩运，异型细胞器融合和溶酶体功能对于自噬体降解的终末阶段至关重要。 A-LS已显示在清除错误折叠的，易于蛋白质的蛋白（如α-突触核蛋白和Huntingtin）中起着重要作用。总的来说，我们假设UPS已更新以在疾病早期清除错误折叠的Tau物种，但是随着Tau丙烯酸的较大骨料的较大骨料，该系统变得不知所措。我们设想，然后将A-LS更新以弥补损失的UPS活动并清除聚集体，但最终两种系统都无法实现，从而导致了加速的病理和衰落。 TAU的积累，UPS与A-LS之间的相互作用以及相关药理学操作对与人陶氏症相关的结果指标的影响之间的关系将在三个特定目标中进行评估。 AIM 1将检查4R tauopathies患者的UPS，Al-S和TAU积累之间的相互作用，并将其与已修饰以表达自噬标记的两种小鼠模型相比。小鼠模型将使我们能够操纵自噬途径的组成部分，以进一步研究与UPS的相互作用，并具体研究了特定泛素化蛋白的发生的情况，以确认自噬充足性在体内tauopathy的进展中的重要性。 AIM 2将使用预先提到的动物模型中的原发性神经元来测试功能障碍在特定途径（自噬真空吸尘器的异常运输，导致自噬通量失败的异常运输）及其对tauopathy的影响，以及对激活A-LS激活A-LS或降低高磷酸化乳磷酸化含水层的病态的影响。 AIM 3将确定使用MLPCN（分子库探针中心网络）通过NCGC/NIH（国家化学和遗传中心）鉴定的化合物是否可以减少亨廷顿蛋白聚集体和细胞死亡是可行的自噬增强子，可用于治疗tauopathy。累积地，这些研究将增加对清除途径，如何和何时失败以及靶向自噬作为对tauopathies的治疗干预的药物的影响的见解。