Accumulation of protein O‐GlcNAc modification inhibits proteasomes in the brain and coincides with neuronal apoptosis in brain areas with high O‐GlcNAc metabolism

All tissues contain the enzymes that modify and remove O‐GlcNAc dynamically from nucleocytoplasmic proteins. These enzymes have been shown to play a role in the control of transcription, vesicular trafficking and, more recently, proteasome function. Modification by O‐GlcNAc of the 19S cap of the proteasome inhibits proteasomal function. Transcripts of both O‐GlcNAc transferase and O‐GlcNAcase are very abundant in the brain, with the highest concentrations in hippocampal neurons and Purkinje cells. When the on‐rate of modification is favored over the off‐rate by intraventricular administration of a drug, streptozocin, these areas of the brain display the most rapid accumulation of O‐GlcNAc. Cerebral proteasome function is reduced and ubiquitin and p53 accumulate in these brain regions, with the subsequent activation of a p53‐dependent transgene and the endogenous Mdm2 gene. Later, some hippocampal cells, but not Purkinje cells, undergo apoptosis. These observations suggest that the O‐GlcNAc system may participate in neurodegeneration, particularly in the hippocampus.