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

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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.