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

J Neurochem. 2004 May;89(4):1044-55. doi: 10.1111/j.1471-4159.2004.02389.x.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Acetylglucosamine / metabolism*
  • Acetylglucosaminidase / genetics
  • Animals
  • Apoptosis / drug effects
  • Brain / drug effects
  • Brain / metabolism*
  • Caspase 3
  • Caspases / drug effects
  • Caspases / metabolism
  • Cysteine Endopeptidases / metabolism*
  • Gene Expression Regulation / drug effects
  • Genes, Reporter
  • Hippocampus / drug effects
  • Hippocampus / metabolism
  • Histone Acetyltransferases
  • Injections, Intraventricular
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred Strains
  • Mice, Knockout
  • Multienzyme Complexes / antagonists & inhibitors
  • Multienzyme Complexes / metabolism*
  • N-Acetylglucosaminyltransferases / genetics
  • Neurons / metabolism
  • Nuclear Proteins*
  • Proteasome Endopeptidase Complex
  • Protein Processing, Post-Translational / drug effects
  • Protein Processing, Post-Translational / physiology*
  • Proteins / metabolism*
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins c-mdm2
  • Purkinje Cells / metabolism
  • RNA, Messenger / metabolism
  • Streptozocin / pharmacology
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism
  • Ubiquitin / metabolism
  • beta-N-Acetylhexosaminidases

Substances

  • Multienzyme Complexes
  • Nuclear Proteins
  • Proteins
  • Proto-Oncogene Proteins
  • RNA, Messenger
  • Tumor Suppressor Protein p53
  • Ubiquitin
  • Streptozocin
  • Histone Acetyltransferases
  • Mdm2 protein, mouse
  • Proto-Oncogene Proteins c-mdm2
  • N-Acetylglucosaminyltransferases
  • O-GlcNAc transferase
  • hexosaminidase C
  • Acetylglucosaminidase
  • beta-N-Acetylhexosaminidases
  • Casp3 protein, mouse
  • Caspase 3
  • Caspases
  • Cysteine Endopeptidases
  • Proteasome Endopeptidase Complex
  • Acetylglucosamine