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Tau post-translational modifications in wild-type and human amyloid precursor protein transgenic mice

Nature Neuroscience volume 18, pages 11831189 (2015) | Download Citation

Abstract

The microtubule-associated protein tau has been implicated in the pathogenesis of Alzheimer's disease (AD) and other neurodegenerative disorders. Reducing tau levels ameliorates AD-related synaptic, network, and behavioral abnormalities in transgenic mice expressing human amyloid precursor protein (hAPP). We used mass spectrometry to characterize the post-translational modification of endogenous tau isolated from wild-type and hAPP mice. We identified seven types of tau modifications at 63 sites in wild-type mice. Wild-type and hAPP mice had similar modifications, supporting the hypothesis that neuronal dysfunction in hAPP mice is enabled by physiological forms of tau. Our findings provide clear evidence for acetylation and ubiquitination of the same lysine residues; some sites were also targeted by lysine methylation. Our findings refute the hypothesis of extensive O-linked N-acetylglucosamine (O-GlcNAc) modification of endogenous tau. The complex post-translational modification of physiological tau suggests that tau is regulated by diverse mechanisms.

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Acknowledgements

We thank M. Finucane for help with the statistical analysis, S. Lee, W. Guo, J. Kang, X. Wang, D. Kim and G.-Q. Yu for technical assistance, S. Ordway for editorial assistance, and M. Dela Cruz and A. Cheung for administrative assistance. The study was supported by US National Institutes of Health grants to L.M. (NS041787) and to A.L.B. (GM103481).

Author information

Author notes

    • Jonathan C Trinidad

    Present address: Department of Chemistry, Indiana University, Bloomington, Indiana, USA.

    • Meaghan Morris
    •  & Giselle M Knudsen

    These authors contributed equally to this work.

Affiliations

  1. Gladstone Institute of Neurological Disease, San Francisco, California, USA.

    • Meaghan Morris
    • , Sumihiro Maeda
    •  & Lennart Mucke
  2. Biochemistry, Cellular and Molecular Biology Graduate Program, Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

    • Meaghan Morris
  3. Mass Spectrometry Facility, Department of Pharmaceutical Chemistry, University of California, San Francisco, California, USA.

    • Giselle M Knudsen
    • , Jonathan C Trinidad
    • , Alexandra Ioanoviciu
    •  & Alma L Burlingame
  4. Department of Neurology, University of California, San Francisco, California, USA.

    • Sumihiro Maeda
    •  & Lennart Mucke

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Contributions

M.M. designed and conducted the mouse experiments, the statistical analyses and wrote the manuscript. G.M.K. analyzed and curated the PTM mapping data, conducted the quantitative mass spectrometry experiments and wrote the manuscript. S.M. conducted PSD fractionation and western blots, and wrote the manuscript. J.C.T. assisted in mass spectrometry method development and wrote the manuscript. A.I. conducted PTM mapping experiments by mass spectrometry. A.L.B. and L.M. supervised the project and wrote the manuscript.

Competing interests

L.M. receives research support from Bristol-Myers Squibb.

Corresponding author

Correspondence to Lennart Mucke.

Integrated supplementary information

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–4

  2. 2.

    Supplementary Methods Checklist

Excel files

  1. 1.

    Supplementary Table 1

    Summary of experiments used to identify post-translational modifications of tau (reporting data available for viewing through MASSive).

  2. 2.

    Supplementary Table 2

    Peptide identifications for modified and unmodified species of tau (data also provided in MS-Viewer format).

  3. 3.

    Supplementary Table 3

    Summary of OGlcNAc-Modified Peptides Identified by LWAC Enrichment.

  4. 4.

    Supplementary Table 4

    Mouse cohorts used for quantitative experiments.

  5. 5.

    Supplementary Table 5

    Quantified tau peptides from hippocampal and cortical whole lysate of cohort A (data also provided in MS-Viewer format).

  6. 6.

    Supplementary Table 6

    Quantified tau peptides from hippocampal and cortical whole lysate, and the post-synaptic density fraction of cohort B (data also provided in MS-Viewer format).

  7. 7.

    Supplementary Table 7

    Quantified tau peptides from post-synaptic density fraction of cohort D (data also provided in MS-Viewer format).

  8. 8.

    Supplementary Table 8

    Quantified tau peptides from post-synaptic density fraction of cohort E (data also provided in MS-Viewer format).

  9. 9.

    Supplementary Table 9

    Comparison of tau modifications identified in this study and previously reported modifications identified in mouse/rat or human brain tissue.

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DOI

https://doi.org/10.1038/nn.4067

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