Human and rodent temporal lobe epilepsy is characterized by changes in O-GlcNAc homeostasis that can be reversed to dampen epileptiform activity

Abstract

Temporal Lobe Epilepsy (TLE) is frequently associated with changes in protein composition and post-translational modifications (PTM) that exacerbate the disorder. O-linked-β-N-acetyl glucosamine (O-GlcNAc) is a PTM occurring at serine/threonine residues that is derived from and closely associated with metabolic substrates. The enzymes O-GlcNActransferase (OGT) and O-GlcNAcase (OGA) mediate the addition and removal, respectively, of the O-GlcNAc modification. The goal of this study was to characterize OGT/OGA and protein O-GlcNAcylation in the epileptic hippocampus and to determine and whether direct manipulation of these proteins and PTM's alter epileptiform activity. We observed reduced global and protein specific O-GlcNAcylation and OGT expression in the kainate rat model of TLE and in human TLE hippocampal tissue. Inhibiting OGA with Thiamet-G elevated protein O-GlcNAcylation, and decreased both seizure duration and epileptic spike events, suggesting that OGA may be a therapeutic target for seizure control. These findings suggest that loss of O-GlcNAc homeostasis in the kainate model and in human TLE can be reversed via targeting of O-GlcNAc related pathways.

O-GlcNAc and EZH2-mediated epigenetic regulation of gene expression during consolidation of fear memories

“…As a result, O-GlcNAcylation has been observed to function as a signal integrator regulating virtually every aspect of cellular function including transcription, translation, signal transduction, and metabolism. Consistent with these observations, disruption of OGT signaling and O-GlcNAcylation processes has been implicated in numerous neurodegenerative diseases, including epilepsy (Sánchez et al 2019), Alzheimer's disease (Xie et al 2016), and Parkinson's disease (Wani et al 2017).…”

“…For example, memory deficits are common in patients with epilepsy, especially temporal lobe epilepsy, where memory-related brain structures such as the hippocampus are directly involved in the processes of epileptogenesis (Tramoni-Negre et al 2017). We have recently reported that O-GlcNAcylation and OGT expression are depleted in the hippocampi of the kainate temporal lobe epilepsy rat model, as well as in human patients with temporal lobe epilepsy (Sánchez et al 2019). Thus, the idea of OGT signaling as a therapeutic target, merits further discussion, as does the impact of O-GlcNAc modification on epigenetic regulation of gene transcription and hippocampusdependent long-term memory formation.…”

Increased O-GlcNAcylation rapidly decreases GABAAR currents in hippocampus yet depresses neuronal output

“…As such, O-GlcNAcylation is positioned to operate as a nutrient sensor (for review, see Lagerlöf, 2018). Additionally, O-GlcNAcylation plays a crucial role in pathological states such as diabetes (Erickson et al, 2013;Vaidyanathan and Wells, 2014) where its elevation can contribute to disease pathogenesis, in epilepsy where increasing O-GlcNAc is protective (Sánchez et al, 2019;Stewart et al, 2017), and in neurodegeneration (Levine etal., 2019;Wang et al, 2016;Yuzwa and Vocadlo, 2014;Yuzwa et al, 2008Yuzwa et al, , 2012Yuzwa et al, , 2014aYuzwa et al, , 2014bZhu et al, 2014), where increasing O-GlcNAc can decrease pathological accumulation of phosphorylated tau or α-synuclein. Collectively, studies published by us and others suggest that maintaining proper balance in O-GlcNAcylation is critical to maintaining normal hippocampal function, as too much or too little O-GlcNAc has been linked to deficits in learning and memory (Taylor et al 2014;Wang et al 2016).…”

Effect of Caffeine and Other Methylxanthines on Aβ-Homeostasis in SH-SY5Y Cells

“…The following additional loading controls were used to determine whether potential differences were due to alterations in protein loading of the western blot (WB): For secreted proteins medium was supplemented with bovine serum albumin (BSA) and detected via Ponceau staining as described in [48]. In lysates actin WB was used as a loading control (anti-actin antibody ab1801 (1:1000; abcam, Cambridge, UK) [49]. For immune precipitation experiments Immunoglobulin G (IgG) antibody signals were quantified and used as an internal loading control as described in [50].…”