All ETDs from UAB

Advisory Committee Chair

Farah D Lubin

Advisory Committee Members

John Chatham

Vladimir Parpura

Lawrence Ver Hoef

Adam Wende

Document Type

Dissertation

Date of Award

2019

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Epilepsy is a neurological disorder that affects roughly 3 million Americans and 65 million individuals worldwide. Although there are several known causes of epilepsy, little is understood about the development of epilepsy or epileptogenesis. What has been observed through multiple studies of epilepsy is an alteration of the proteomic profile, along with a distinct change in post-translational modifications (PTM). Studies have focused on phosphorylation and a variety of kinases that are upregulated during epilepsy with little clinical translation. This dissertation investigates O-GlcNAcylation, a PTM that is highly intertwined with the cellular metabolism, and its epigenetic effects on gene expression via 5-hydroxymethylcytosine (5hmC) expression in the epileptic hippocampus. We found that in epilepsy global O-GlcNAcylation is downregulated, as well as global 5hmC. Furthermore, there were profound changes decreases in seizures, seizure duration, and severity when O-GlcNAcylation was promoted in epileptic animals. Therefore, we hypothesized that the global loss of O-GlcNAcylation disrupted genomic and gene-specific 5hmC DNA marks that promoted aberrant gene and protein expression associated with epilepsy. In support of our hypothesis, we found that promoting and restoring global O-GlcNAcylation with Thiamet-G in epileptic rats restored the genomic loss of 5hmC. In addition, treatment with Thiamet-G displayed preferential restoration of 5hmC at promoter and gene body regions of anti-convulsive genes associated with epilepsy. Interestingly, treatment with Thiamet-G had a seizure dampening effect but demonstrated little impact in decreasing/reversing ventricle enlargement. Altogether, our findings have begun to elucidate a novel association between PTM’s and epigenetic gene regulation in epilepsy that can demonstrate the therapeutic potential to alleviate the disorder.

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