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

Lookup NU author(s): Ryley Parrish, Dr Alistair Jenkins, Mark Cunningham


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© 2019 Elsevier Inc. 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.

Publication metadata

Author(s): Sanchez RG, Parrish RR, Rich M, Webb WM, Lockhart RM, Nakao K, Ianov L, Buckingham SC, Broadwater DR, Jenkins A, de Lanerolle NC, Cunningham M, Eid T, Riley K, Lubin FD

Publication type: Article

Publication status: Published

Journal: Neurobiology of Disease

Year: 2019

Volume: 124

Pages: 531-543

Print publication date: 01/04/2019

Online publication date: 06/01/2019

Acceptance date: 01/01/2019

ISSN (print): 0969-9961

ISSN (electronic): 1095-953X

Publisher: Academic Press Inc.


DOI: 10.1016/j.nbd.2019.01.001


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