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Investigating autophagic degradation of tau mediated by polyubiquitination

研究多泛素化介导的 tau 自噬降解

基本信息

批准号：
10432378
负责人：
Zhihao Zhuang
金额：
$ 42.36万
依托单位：
UNIVERSITY OF DELAWARE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10432378
关键词：
Address Affect Affinity Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer&apos s disease therapeutic Alzheimer’s disease biomarker Amyloid Proteins Amyloid beta-Protein Attention Autophagocytosis Autopsy Binding Biochemical Biological Assay Biology Brain Cell physiology Cells Chemicals Cognitive Coupled Cryoelectron Microscopy Deterioration Deubiquitination Development Disease Fluorescence Homeostasis Human Individual Intervention Lesion Link Lysine Lysosomes Mass Spectrum Analysis Mediating Microglia Microtubules Nature Neurofibrillary Tangles Neurons Pathway interactions Pharmacology Physiological Play Polyubiquitin Polyubiquitination Preparation Process Proteins Proteomics Reducing Agents Research Resistance Role Sampling Seminal Senile Plaques Site Small Interfering RNA Structure Tauopathies Therapeutic Ubiquitin Ubiquitination base biophysical techniques brain tissue electron density extracellular frontal lobe hyperphosphorylated tau knock-down nervous system disorder novel overexpression potential biomarker prevent receptor tau Proteins tau aggregation tau function thioether ubiquitin ligase

项目摘要

Investigating autophagic degradation of tau mediated by polyubiquitination Aberrant degradation and accumulation of tau in human brains is intimately connected to the development of Alzheimer’s disease (AD). Attentions are now directed to the cellular pathways responsible for the clearance of tau from neuronal cells, particularly through the autophagy-lysosome pathway. K63-linked polyubiquitination of tau is intimately involved in the early stage of autophagic degradation of tau. Compared to the better studied proteasomal degradation of tau, the recognition of tau by the autophagic machinery and the subsequent degradation by lysosome is poorly understood. Mechanistic details and in-depth biochemical characterization of the individual players and steps in this process are lacking. How the K63-linked polyubiquitination of tau mediates its autophagic degradation is largely unknown. Moreover, our understanding of tau deubiquitination and its role in regulating tau homeostasis is still very limited. We will address these unanswered questions using K63-polyUb-tau probes generated using a semi-synthetic approach to capture and identify cognate autophagic receptors and deubiquitinases that are responsible for modulation of the autophagic degradation of tau. Our findings will unveil new biology in this cellular process and provide potential new targets for pharmacological intervention of AD.

研究多聚泛素化介导的tau蛋白自噬降解人类大脑中tau蛋白的异常降解和积累与大脑中tau蛋白的表达密切相关。阿尔茨海默病（AD）的发展。现在，注意力被引导到负责从神经元细胞中清除tau，特别是通过自噬-溶酶体途径。K63连锁 tau的多泛素化密切参与tau的自噬降解的早期阶段。相比更好地研究了tau蛋白酶体降解、自噬机制对tau蛋白的识别，对随后的溶酶体降解了解甚少。机械细节和深入的生化缺乏对这一进程中的各个行为者和步骤的定性。K63如何与 tau蛋白的多泛素化介导其自噬降解在很大程度上是未知的。此外，我们的理解 tau蛋白去泛素化及其在调节tau蛋白稳态中的作用仍然非常有限。我们将解决这些问题使用半合成方法产生的K63-polyUb-tau探针来捕获和鉴定同源自噬受体和负责调节自噬的去泛素化酶， tau的降解。我们的发现将揭示这一细胞过程中的新生物学，并提供潜在的新靶点。用于AD的药物干预。