O-GLCNAC HOMEOSTASIS REGULATES MITOCHONDRIAL FUNCTION IN ALZHEIMER'S DISEASE

O-GLCNAC 稳态调节阿尔茨海默病的线粒体功能

基本信息

批准号：
10391474
负责人：
Chad Eric Slawson
金额：
$ 64.2万
依托单位：
UNIVERSITY OF KANSAS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10391474
关键词：
Address Affect Aftercare Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer’s disease biomarker American Amino Acids Amyloid Antioxidants Cell Cycle Cell Line Cell physiology Cells Chronic Citric Acid Cycle Clinical Pathways Cues Cytoplasmic Protein Data Development Diagnostic Disease Disease Progression Electron Transport Environment Enzymes Etiology Gene Expression Genes Genetic Transcription Glucosamine Homeostasis Hormones Impairment Inflammation Intervention Link Mass Spectrum Analysis Measures Metabolic Metabolic Diseases Metabolic dysfunction Methods Mitochondria Mitochondrial Proteins Modification Morphology Mus Nuclear Proteins Nutrient O-GlcNAc transferase Oxidative Stress Physiology Post-Translational Protein Processing Prevention Production Proteins Proteome Proteomics Public Health Publishing Reactive Oxygen Species Regulation Research Respiration Role Sampling Serine Signal Transduction Site Symptoms Testing Threonine Tissues Translations age related animal tissue biological adaptation to stress cell injury diagnostic biomarker environmental change extracellular inhibitor knock-down mitochondrial dysfunction mouse model neurofibrillary tangle formation neuronal metabolism novel novel therapeutics nuclear factor-erythroid 2 overexpression peptide O-linked N-acetylglucosamine-beta-N-acetylglucosaminidase protein expression response spatial memory tau Proteins transcription factor transcriptome

项目摘要

Currently, 5.4 million Americans are suffering from Alzheimer’s disease (AD), which is the only major disease lacking good prevention methods, treatments, or a cure. Recent evidence suggests that age related impairment of mitochondrial function and increased reactive oxygen species (ROS) production contribute to cellular damage and AD progression. The object of this proposal is to understand the affects of O-GlcNAcylation on mitochondrial function and the development of AD. O-GlcNAc is categorized by the addition of a single O-linked β-N-acetyl-D-glucosamine moiety to serine/threonine amino acids of nuclear and cytoplasmic proteins. This modification is responsive to extracellular signals such hormones, nutrients, and environmental cues and is involved in regulating numerous cellular functions such as the cell cycle, stress response, transcription, and translation. The enzymes responsible for processing the modification are O-GlcNAc transferase (OGT), which adds the modification, and O-GlcNAcase (OGA), which removes the modification. Importantly, changes in O-GlcNAcylation alter mitochondrial function. Cells actively maintain homeostatic levels in O-GlcNAc, and cells will alter the expression of OGT and OGA to modulate O-GlcNAcylation due to changes in the environment. We contend that O-GlcNAcylation is disrupted in chronic metabolic disease, which exacerbates the decline in mitochondrial function. We have demonstrated that over-expression of OGT or OGA causes large changes in protein expression of electron transport chain and Krebs cycle proteins, respiration is impaired, and mitochondrial morphology is disrupted. These data suggest that alterations to O-GlcNAc homeostasis would affect mitochondrial function exacerbating AD. In the current proposal, we will determine the mechanisms as to how O-GlcNAcylation regulates cellular function. First, we will identify changes to the transcriptome, proteome, and O-GlcNAcome in mouse models of AD or after loss of OGT. We will then determine how disrupted O-GlcNAc homeostasis affects electron transport chain function and metabolic gene expression. We will address the effect of OGA inhibitors on ameliorating mitochondrial dysfunction in AD mouse models. Furthermore, we will explore how O-GlcNAcylation influences mitochondrial anti-oxidant response. Our preliminary data shows that alterations in O-GlcNAc induce changes in anti-oxidant response and NRF2 activity, a critical transcription factor controlling the transcription of anti-oxidant genes. We will ascertain the mechanistic role of O-GlcNAc in regulating NRF2 transcriptional activity and protein interactions. Finally, we will use AD patient samples to identify the potential to use of O-GlcNAc, OGT or OGA as AD biomarkers. These studies will provide new mechanistic details into how O-GlcNAcylation affects mitochondrial function, how O-GlcNAc influences anti-oxidant response, NRF2 function, and will provide new pathways for clinical intervention of AD.

目前，540万美国人患有阿尔茨海默病（AD），这是唯一的主要疾病缺乏良好的预防方法、治疗或治愈方法最近的证据表明，这与年龄有关。线粒体功能受损和活性氧（ROS）产生增加有助于该提案的目的是了解 O-GlcNAc 酰化对线粒体功能的影响，并按添加对 O-GlcNAc 的发展进行分类。单个O-连接的β-N-乙酰基-D-葡萄糖胺部分与核和核的丝氨酸/苏氨酸氨基酸这种修饰对细胞外信号如激素、营养物质和环境因素并参与调节许多细胞功能，如细胞周期、压力负责处理修饰的酶是 O-GlcNAc 转移酶 (OGT)（添加修饰）和 O-GlcNAcase (OGA)（去除修饰）。重要的是，O-GlcNAcylation 的变化会改变细胞的线粒体功能。由于环境的变化，O-GlcNAc 的稳态水平会改变 OGT 和 OGA 的表达来调节 O-GlcNAc 化，我们认为 O-GlcNAc 化在慢性过程中受到破坏。代谢疾病，这会加剧线粒体功能的下降，我们已经证明 OGT 或 OGA 的过度表达会导致电子传递链和克雷布斯的蛋白质表达发生巨大变化。循环蛋白质、呼吸受损、线粒体形态被破坏。这些数据表明。 O-GlcNAc 稳态的改变会影响线粒体功能，从而加剧目前的 AD。提案中，我们将确定 O-GlcNAcylation 如何调节细胞功能的机制。将识别 AD 小鼠模型中或 AD 缺失后转录组、蛋白质组和 O-GlcNAcome 的变化然后我们将确定 O-GlcNAc 稳态被破坏如何影响电子传递链功能。我们将讨论 OGA 抑制剂对改善线粒体的影响。此外，我们将探讨 O-GlcNAcylation 如何影响线粒体。我们的初步数据表明，O-GlcNAc 的改变会引起抗氧化反应的变化。 NRF2 活性是控制抗氧化基因转录的关键转录因子。将确定 O-GlcNAc 在调节 NRF2 转录活性和蛋白质中的机制作用最后，我们将使用 AD 患者样本来确定 O-GlcNAc、OGT 或 OGA 的使用潜力。作为 AD 生物标志物，这些研究将为 O-GlcNAcylation 如何影响提供新的机制细节。线粒体功能、O-GlcNAc 如何影响抗氧化反应、NRF2 功能，并将提供新的 AD临床干预途径