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bioRxiv · 10.1101/330738

Human and Rodent Temporal Lobe Epilepsy is Characterized by Changes in O-GlcNAc Homeostasis that can be Reversed to Dampen Epileptiform Activity

Sanchez, R. G.·Parrish, R. R.·Rich, M. C.·Webb, W. M.·Lockhart, R. M.·Nakao, K.·Ianov, L.·Buckingham, S. C.·Cunningham, M.·Broadwater, D. R.·Jenkins, A.·De Lanerolle, N. C.·Eid, T.·Riley, K.·Lubin, F. D.
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Abstract

Temporal Lobe Epilepsy (TLE) is frequently associated with changes in protein composition and post-translational modifications (PTM) that exacerbate the disorder. O-linked-{beta}-N-acetyl glucosamine (O-GlcNAc) is a PTM occurring at serine/threonine residues that integrate energy supply with demand. 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 determine whether changes in OGT/OGA cycling and disruptions in protein O-GlcNAcylation occur in the epileptic hippocampus. 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.

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Sanchez, R. G., Parrish, R. R., Rich, M. C., Webb, W. M., Lockhart, R. M., Nakao, K., Ianov, L., Buckingham, S. C., Cunningham, M., Broadwater, D. R., Jenkins, A., De Lanerolle, N. C., Eid, T., Riley, K., Lubin, F. D.. 2018-05-31. Human and Rodent Temporal Lobe Epilepsy is Characterized by Changes in O-GlcNAc Homeostasis that can be Reversed to Dampen Epileptiform Activity. https://doi.org/10.1101/330738

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