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Increasing O-GlcNAc slows neurodegeneration and stabilizes tau against aggregation

Nature Chemical Biology volume 8, pages 393–399 (2012)Cite this article

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Abstract

Oligomerization of tau is a key process contributing to the progressive death of neurons in Alzheimer's disease. Tau is modified by O-linked N-acetylglucosamine (O-GlcNAc), and O-GlcNAc can influence tau phosphorylation in certain cases. We therefore speculated that increasing tau O-GlcNAc could be a strategy to hinder pathological tau-induced neurodegeneration. Here we found that treatment of hemizygous JNPL3 tau transgenic mice with an O-GlcNAcase inhibitor increased tau O-GlcNAc, hindered formation of tau aggregates and decreased neuronal cell loss. Notably, increases in tau O-GlcNAc did not alter tau phosphorylation in vivo. Using in vitro biochemical aggregation studies, we found that O-GlcNAc modification, on its own, hinders tau oligomerization. O-GlcNAc also inhibits thermally induced aggregation of an unrelated protein, TAK-1 binding protein, suggesting that a basic biochemical function of O-GlcNAc may be to prevent protein aggregation. These results also suggest O-GlcNAcase as a potential therapeutic target that could hinder progression of Alzheimer's disease.

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Figure 1: Treatment of JNPL3 mice increases global and tau O-GlcNAc and reduces neurodegeneration.
Figure 2: IHC analysis of thiamet-G–treated JNPL3 mice reveals reductions in NFTs.
Figure 3: Biochemical analysis of thiamet-G–treated JNPL3 mice.
Figure 4: O-GlcNAc on Tau244–441 slows aggregation in vitro.

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Acknowledgements

We thank the Scottish Rite Charitable Foundation, the Canadian Institutes of Health Research (CIHR) and the Alzheimer Society of Canada for financial support of this research. The Canada Research Chairs program, the Michael Smith Foundation for Health Research (MSFHR) and the Natural Sciences and Engineering Research Council of Canada (NSERC, E.W.R. Steacie Award) are thanked for awards to D.J.V. NSERC is thanked for an award to S.A.Y. The MSFHR and the CIHR are thanked for awards to X.S. The MSFHR, NSERC and Human Frontier Science Program are thanked for awards to M.S.M. We thank the staff at the animal care facility at Simon Fraser University for assistance with the animal studies. P. Davies (Albert Einstein College of Medicine) is thanked for the kind gift of the CP27 and PHF-1 antibodies used in this work. Y. Deng, R. Kaul and E. McEachern are thanked for assistance with preliminary studies, large-scale synthesis of thiamet-G and productive discussion.

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Author notes

  1. Matthew S Macauley

    Present address: Current address: Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California, USA.,

  2. Scott A Yuzwa and Xiaoyang Shan: These authors contributed equally to this work.

Authors and Affiliations

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

    Scott A Yuzwa, Xiaoyang Shan & David J Vocadlo

  2. Department of Chemistry, Simon Fraser University, Burnaby, British Columbia, Canada

    Matthew S Macauley, Thomas Clark & David J Vocadlo

  3. Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA

    Yuliya Skorobogatko & Keith Vosseller

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Contributions

D.J.V. directed the study. S.A.Y., X.S., M.S.M. and D.J.V. designed the experiments. X.S. conducted the rotarod assessment and the JNPL3 IHC. S.A.Y. conducted the cage hang test and the JNPL3 tau biochemistry and tau in vitro aggregation experiments. M.S.M. conducted the sTAB1 experiments. Y.S., T.C. and K.V. conducted the tau mass spectrometry. S.A.Y., X.S. and D.J.V. wrote the manuscript.

Corresponding author

Correspondence to David J Vocadlo.

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Competing interests

S.A.Y., M.S.M., X.S. and D.J.V. are eligible to receive royalties from Simon Fraser University. D.J.V. is a founder, shareholder, consultant and member of the scientific advisory board of Alectos Therapeutics.

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Yuzwa, S., Shan, X., Macauley, M. et al. Increasing O-GlcNAc slows neurodegeneration and stabilizes tau against aggregation. Nat Chem Biol 8, 393–399 (2012). https://doi.org/10.1038/nchembio.797

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