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

Academic Article

Abstract

  • 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.
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    Digital Object Identifier (doi)

    Author List

  • Liu K; Paterson AJ; Zhang F; McAndrew J; Fukuchi KI; Wyss JM; Peng L; Hu Y; Kudlow JE
  • Start Page

  • 1044
  • End Page

  • 1055
  • Volume

  • 89
  • Issue

  • 4