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Neurobiol Dis. 2019 Jan 6;124:531-543. doi: 10.1016/j.nbd.2019.01.001. [Epub ahead of print]

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

Author information

1
Department of Neurobiology, University of Alabama, Birmingham, AL, United States.
2
Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK.
3
Civitan International Research Center, University of Alabama, Birmingham, AL, United States.
4
School of Medicine, University of Alabama, Birmingham, AL, United States.
5
Department of Neurosurgery, Royal Victoria Infirmary, Newcastle upon Tyne NE1 4LP, UK.
6
Department of Laboratory Medicine and of Neurosurgery, Yale School of Medicine, New Haven, CT, United States.
7
Department of Neurosurgery, University of Alabama, Birmingham, AL, United States.
8
Department of Neurobiology, University of Alabama, Birmingham, AL, United States. Electronic address: flubin@uab.edu.

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.

KEYWORDS:

Electroencephalogram; Electrophysiology; Hippocampus; Magnetic resonance imaging; Mass spectrometry; O-GlcNAcylation; Post-translational modification; Thiamet-G

PMID:
30625365
DOI:
10.1016/j.nbd.2019.01.001

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