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

Nature Chemical Biology volume 4, pages 483–490 (2008)Cite this article

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, Ki = 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.

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Figure 1: The relationship between phosphorylation and O-GlcNAcylation on tau is a dynamic equilibrium.
Figure 2: Thiamet-G binds similarly to NButGT and exhibits small structural perturbations.
Figure 3: Thiamet-G inhibits O-GlcNAcase in PC-12 cells in both a dose- and time-dependent manner and reduces tau phosphorylation.
Figure 4: In vivo administration of thiamet-G reduces tau phosphorylation.
Figure 5: In vivo administration of thiamet-G reduces tau phosphorylation in the CA1 region of the hippocampus.

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Acknowledgements

We thank the staff at the Animal Care Facility at Simon Fraser University and Y. Deng for assistance with the animal studies. T. Gloster is thanked for assistance with the X-ray structural studies. We also thank the Canadian Institute for Health Research (CIHR), the Scottish Rite Charitable Foundation (SRCF) and the Biotechnology and Biological Sciences Research Council (BBSRC) for providing funding for this work. M.S.M. and X.S. are recipients of senior scholarships from the Michael Smith Foundation for Health Research (MSFHR). X.S. is a doctoral research scholarship holder from the CIHR and the ALS Society of Canada. M.S.M. is also a scholarship holder from the Natural Science and Engineering Research Council of Canada (NSERC). Y.H. is the recipient of University of York Wild Fund support. G.J.D. is a Royal Society-Wolfson Research Merit Award recipient. D.J.V. is a scholar of the MSFHR and the Canada Research Chair in Chemical Glycobiology.

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Authors and Affiliations

  1. Department of Molecular Biology and Biochemistry, Simon Fraser University, 8888 University Drive, Burnaby, V5A 1S6, British Columbia, Canada

    Scott A Yuzwa, Xiaoyang Shan & David J Vocadlo

  2. Department of Chemistry, Simon Fraser University, 8888 University Drive, Burnaby, V5A 1S6, British Columbia, Canada

    Matthew S Macauley, Julia E Heinonen, Garrett E Whitworth, Keith A Stubbs, Ernest J McEachern & David J Vocadlo

  3. Department of Chemistry, York Structural Biology Laboratory, The University of York, Heslington, YO10 5YW, York, UK

    Rebecca J Dennis, Yuan He & Gideon J Davies

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Correspondence to David J Vocadlo.

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Yuzwa, S., Macauley, M., Heinonen, J. et al. A potent mechanism-inspired O-GlcNAcase inhibitor that blocks phosphorylation of tau in vivo. Nat Chem Biol 4, 483–490 (2008). https://doi.org/10.1038/nchembio.96

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