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.
Liu
Kan
K
Department Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Alabama at Birmingham, 35294, USA.
Paterson
Andrew J
AJ
Zhang
Fengxue
F
McAndrew
Joanne
J
Fukuchi
Ken-Ichiro
K
Wyss
J Michael
JM
Peng
Ling
L
Hu
Yong
Y
Kudlow
Jeffrey E
JE
D000117:Acetylglucosamine / Q000378:metabolism*; D000118:Acetylglucosaminidase / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D053148:Caspase 3; D020169:Caspases / Q000187:drug effects / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D017930:Genes, Reporter; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D051548:Histone Acetyltransferases; D007276:Injections, Intraventricular; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics; D009474:Neurons / Q000378:metabolism; D009687:Nuclear Proteins; D046988:Proteasome Endopeptidase Complex; D011499:Protein Processing, Post-Translational / Q000187:drug effects / Q000502:physiology*; D011506:Proteins / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics; D051736:Proto-Oncogene Proteins c-mdm2; D011689:Purkinje Cells / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D013311:Streptozocin / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism; D001619:beta-N-Acetylhexosaminidases
D009097:Multienzyme Complexes; D009687:Nuclear Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D025801:Ubiquitin; D013311:Streptozocin; D051548:Histone Acetyltransferases; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; D017351:N-Acetylglucosaminyltransferases; C449880:O-GlcNAc transferase; C110628:hexosaminidase C; D000118:Acetylglucosaminidase; D001619:beta-N-Acetylhexosaminidases; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D000117:Acetylglucosamine