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（申请人证明）：错误折叠蛋白的细胞内夹杂物是许多神经修复的标志。疾病的发展。对于a-戈果质量降解的终端至关重要。 tau积累。然后，我们设想A-LS是为了补偿丢失的UPS活动并清除聚集体，但最终两个系统都会导致病理加速和衰落之间的关系。 UPS和A-LS人的tauopathy将在三个特定目标中评估，并在4R tauopathies中积累，并与已修改的4R小鼠模型进行比较允许我们操纵自噬途径的组成部分，以进一步研究UPS的相互作用。导致自噬通量失败及其对tauopathy的影响，以及激活A-LS的化合物是否会减轻病理表型的过度磷酸化tau的水平。）减少亨廷顿和细胞死亡的是可能的自噬增强子