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A potent mechanism-inspired O-GlcNAcase inhibitor that blocks phosphorylation of tau in vivo

Research output: Contribution to journalArticle

Author(s)

  • Scott A. Yuzwa
  • Matthew S. Macauley
  • Julia E. Heinonen
  • Xiaoyang Shan
  • Rebecca J. Dennis
  • Yuan He
  • Garrett E. Whitworth
  • Keith A. Stubbs
  • Ernest J. McEachern
  • Gideon J. Davies
  • David J. Vocadlo

Department/unit(s)

Publication details

JournalNATURE CHEMICAL BIOLOGY
DatePublished - Aug 2008
Issue number8
Volume4
Number of pages8
Pages (from-to)483-490
Original languageEnglish

Abstract

Pathological hyperphosphorylation of the microtubule-associated protein tau is characteristic of Alzheimer's disease (AD) and the associated tauopathies. The reciprocal relationship between phosphorylation and O-GlcNAc modification of tau and reductions in O-GlcNAc levels on tau in AD brain offers motivation for the generation of potent and selective inhibitors that can effectively enhance O-GlcNAc in vertebrate brain. We describe the rational design and synthesis of such an inhibitor (thiamet-G, K-i = 21 nM; 1) of human O-GlcNAcase. Thiamet-G decreased phosphorylation of tau in PC-12 cells at pathologically relevant sites including Thr231 and Ser396. Thiamet-G also efficiently reduced phosphorylation of tau at Thr231, Ser396 and Ser422 in both rat cortex and hippocampus, which reveals the rapid and dynamic relationship between O-GlcNAc and phosphorylation of tau in vivo. We anticipate that thiamet-G will find wide use in probing the functional role of O-GlcNAc in vertebrate brain, and it may also offer a route to blocking pathological hyperphosphorylation of tau in AD.

    Research areas

  • BETA-N-ACETYLGLUCOSAMINIDASE, PAIRED HELICAL FILAMENTS, GLYCOGEN-SYNTHASE KINASE-3-BETA, SUBSTRATE-ASSISTED CATALYSIS, TETRATRICOPEPTIDE REPEATS, NEUROFIBRILLARY TANGLES, ALZHEIMERS-DISEASE, CYTOSOLIC PROTEINS, D-GLUCOSAMINIDASE, NAG-THIAZOLINE

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