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

Academic Article
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Overview

authors

  • Yuzwa, S. A.
  • Macauley, Matthew
  • Heinonen, J. E.
  • Shan, X.
  • Dennis, R. J.
  • He, Y.
  • Whitworth, G. E.
  • Stubbs, K. A.
  • McEachern, E. J.
  • Davies, G. J.
  • Vocadlo, D. J.

publication date

  • August 2008

journal

  • Nature Chemical Biology  Journal

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.

subject areas

  • Animals
  • Brain Chemistry
  • Cerebral Cortex
  • Enzyme Inhibitors
  • Hippocampus
  • Humans
  • Phosphorylation
  • Rats
  • Tauopathies
  • beta-N-Acetylhexosaminidases
  • tau Proteins
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Identity

International Standard Serial Number (ISSN)

  • 1552-4450

Digital Object Identifier (DOI)

  • 10.1038/nchembio.96

PubMed ID

  • 18587388
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Additional Document Info

start page

  • 483

end page

  • 490

volume

  • 4

issue

  • 8

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