01 - Exploring the role of O-GlcNAcylation in brain injury
University of Alabama, Birmingham
The post-translational modification of specific serine and threonine residues of nuclear, cytoplasmic, and membrane proteins by the O-linked N-acetylglucosamine (GlcNAc) transferase (OGT) has been shown to play a critical role in the acute regulation of cellular survival as well as in the pathogenesis of several neurological disorders. This study aimed to determine whether manipulating O-GlcNAc levels alters disease course in an experimental model of epilepsy or imporves brain health following traumatic brain injury (TBI) in rats. We found that O-GlcNAc levels were altered in the hippocampus of epileptic rats and in rodents following moderate TBI. O-GlcNAc levels can be increased acutely by inhibiting O-GlcNAcase (OGA), which catalyzes the removal of O-GlcNAc from proteins. One mechanism for rapidly increasing O-GlcNAcylation is by pharmacological inhibition of OGA. A novel and highly specific inhibitor of OGA is now available, thiamet-G. We found that thiamet-G treatment reduced hyperexcitability in our Kainate-injury induced rodent model of epilepsy, which was accompanied with a reversal of reduced 5-Hydroxymethylcytosine (5hmC) DNA methylation levels in the epileptic hippocampus. Importantly, 5hmC is catalyzed by the Ten-eleven translocation (TET) family of enzymes that colocalizes with OGT. Following TBI, we found that at the cellular, organ, and organismal level, increasing protein O-GlcNAc modification with thiamet-G enhanced cell survival and attenuated cell death. Collectively, these findings demonstrate for the first time the potential of thiamet-G as a therapeutic option for treatment of neuronal dysfunction following brain injury.