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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.