Increased O-GlcNAc levels correlate with decreased O-GlcNAcase levels in Alzheimer disease brain

Sarah Förster, Andrew S. Welleford, Judy C. Triplett, Rukhsana Sultana, Brigitte Schmitz, D. Allan Butterfield

Research output: Contribution to journalArticlepeer-review

52 Scopus citations

Abstract

The potential role of the posttranslational modification of proteins with O-linked N-acetyl-β- d-glucosamine (O-GlcNAc) in the pathogenesis of Alzheimer disease (AD) has been studied extensively, yet the exact function of O-GlcNAc in AD remains elusive. O-GlcNAc cycling is facilitated by only two highly conserved enzymes: O-GlcNAc transferase (OGT) catalyzes the addition, while O-GlcNAcase (OGA) catalyzes the removal of GlcNAc from proteins. Studies analyzing global O-GlcNAc levels in AD brain have produced inconsistent results and the reasons for altered O-GlcNAcylation in AD are still poorly understood. In this study, we show a 1.2-fold increase in cytosolic protein O-GlcNAc modification in AD brain when compared to age-matched controls. Interestingly, O-GlcNAc changes seem to be attributable to differential modification of a few individual proteins. While our finding of augmented O-GlcNAcylation concurs with some reports, it is contrary to others demonstrating decreased O-GlcNAc levels in AD brain. These conflicting results emphasize the need for further studies providing conclusive evidence on the subject of O-GlcNAcylation in AD. We further demonstrate that, while OGT protein levels are unaffected in AD, OGA protein levels are significantly decreased to 75% of those in control samples. In addition, augmented protein O-GlcNAc modification correlates to decreased OGA protein levels in AD subjects. While OGA inhibitors are already being tested for AD treatment, our results provide a strong indication that the general subject of O-GlcNAcylation and specifically its regulation by OGA and OGT in AD need further investigation to conclusively elucidate its potential role in AD pathogenesis and treatment.

Original languageEnglish
Pages (from-to)1333-1339
Number of pages7
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1842
Issue number9
DOIs
StatePublished - Sep 2014

Bibliographical note

Funding Information:
The authors thank the University of Kentucky ADC Clinical Neuropathology Core Faculty for providing the brain specimen used for this study. We thank Dr. Garland Crawford and Dr. Shane Arnold for providing antibodies and Dr. Simone Diestel for critical reading of the manuscript. This work was supported in part by a NIH grant to D.A.B. [ AG-05119 ]. The authors state no conflict of interest associated with this study.

Keywords

  • Alzheimer disease
  • O-GlcNAc
  • O-GlcNAcase

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology

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