Abstract

Huntington's disease is a fatal neurodegenerative disorder caused by an expanded polyglutamine repeat in huntingtin (HTT) protein. We previously showed that calorie restriction ameliorated Huntington's disease pathogenesis and slowed disease progression in mice that model Huntington's disease (Huntington's disease mice)1. We now report that overexpression of sirtuin 1 (Sirt1), a mediator of the beneficial metabolic effects of calorie restriction, protects neurons against mutant HTT toxicity, whereas reduction of Sirt1 exacerbates mutant HTT toxicity. Overexpression of Sirt1 improves motor function, reduces brain atrophy and attenuates mutant-HTT–mediated metabolic abnormalities in Huntington's disease mice. Further mechanistic studies suggested that Sirt1 prevents the mutant-HTT–induced decline in brain-derived neurotrophic factor (BDNF) concentrations and the signaling of its receptor, TrkB, and restores dopamine- and cAMP-regulated phosphoprotein, 32 kDa (DARPP32) concentrations in the striatum. Sirt1 deacetylase activity is required for Sirt1-mediated neuroprotection in Huntington's disease cell models. Notably, we show that mutant HTT interacts with Sirt1 and inhibits Sirt1 deacetylase activity, which results in hyperacetylation of Sirt1 substrates such as forkhead box O3A (Foxo3a), thereby inhibiting its pro-survival function. Overexpression of Sirt1 counteracts the mutant-HTT–induced deacetylase deficit, enhances the deacetylation of Foxo3a and facilitates cell survival. These findings show a neuroprotective role for Sirt1 in mammalian Huntington's disease models and open new avenues for the development of neuroprotective strategies in Huntington's disease.

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Acknowledgements

We thank L. Tsai at Massachusetts Institute of Technology for providing Sirt1 and H363Y retrovirus constructs, S. Imai at Washington University for providing Sir2 complementary DNAs (cDNAs), M. Macdonald at Harvard Medical School for providing STHdhQ7/Q7 and STHdhQ111/Q111 cells, S. Li and X. Li at Emory University for providing antibodies to EM48 and E. Waldron, C. Berlinicke, Y. Cheng and J. Jin at Johns Hopkins University School of Medicine for their technical assistance. This work was supported by the Hereditary Disease Foundation (W.D.), CHDI Foundation grant A-2120 (W.D.), NIH grant NS 16375 (C.A.R.), NIH grant NS35902 (D.M.H.), the NIA Intramural Research Program (B.M., H.C., S. Maudesley and M.P.M.), NIH grant R01NS051303 (D.K.), NIH grant EB003543 and ES012665 (S. Mori) and NIH grant NS065306 (J.Z.).

Author information

Author notes

    • Mali Jiang
    •  & Jiawei Wang

    These authors contributed equally to this work.

Affiliations

  1. Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

    • Mali Jiang
    • , Jiawei Wang
    • , Jinrong Fu
    • , Lan Xiang
    • , Qi Peng
    • , Nicolas Arbez
    • , Shanshan Zhu
    • , Katherine Sommers
    • , Jennifer Qian
    • , Christopher A Ross
    •  & Wenzhen Duan
  2. Beijing Friendship Hospital, Capital Medical University, Beijing, China.

    • Jiawei Wang
  3. Natural Products Discovery Group, Department of Chemistry and Biochemistry, University of Oklahoma, Norman, Oklahoma, USA.

    • Lin Du
    •  & Robert H Cichewicz
  4. Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.

    • Hyunkyung Jeong
    •  & Dimitri Krainc
  5. Department of Neurology and the Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, Missouri, USA.

    • Tim West
    •  & David M Holtzman
  6. Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

    • Zhipeng Hou
    • , Jiangyang Zhang
    •  & Susumu Mori
  7. Metabolism Unit, Laboratory of Clinical Investigation, National Institute on Aging (NIA), US National Institutes of Health (NIH), Baltimore, Maryland, USA.

    • Huan Cai
    •  & Bronwen Martin
  8. Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.

    • Tamara Seredenina
    •  & Ruth Luthi-Carter
  9. Department of Psychiatry and Behavioral Sciences, Brain Research Institute, University of California, Los Angeles, California, USA.

    • X William Yang
  10. Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

    • Kellie L K Tamashiro
    •  & Timothy H Moran
  11. Center for Metabolism and Obesity Research, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

    • Susan Aja
  12. Laboratory of Neurosciences, NIA, NIH, Baltimore, Maryland, USA.

    • Stuart Maudsley
    •  & Mark P Mattson
  13. Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

    • Christopher A Ross
  14. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

    • Christopher A Ross
  15. Department of Pharmacology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

    • Christopher A Ross
  16. Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

    • Christopher A Ross
    •  & Wenzhen Duan

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Contributions

M.J. designed and conducted the experiments and interpreted the data. J.W. designed and conducted the experiments in BACHD mice. J.F. contributed to the cell culture experiments. L.D. and R.H.C. performed the HPLC assays. H.-K.J. and D.K. provided the acetylated-lysine antibody and conducted the Sirt1 deacetylase assay. T.W. and D.M.H. provided the Sirt1 mice and the Sirt1 tissue expression data. H.C. contributed to the immunohistochemistry. L.X. and Q.P. conducted behavioral tests. Z.H., J.Z. and S. Mori performed the MRI scans. T.S. and R.L.-C. contributed to the BDNF assays. N.A. carried out the primary neuronal assay. S.Z., K.S. and J.Q. contributed to the coimmunoprecipitation, cell counting and immunohistochemistry. K.L.K.T., S.A., T.H.M., B.M., S. Maudsley and M.P.M. contributed to the metabolic measurements and discussion. X.W.Y. provided the BACHD mice. C.A.R. helped with the conception, design and interpretation of the experiments. D.K. contributed to the discussion and helped with the writing of the paper. W.D. designed, directed and coordinated the project and wrote the paper.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Wenzhen Duan.

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https://doi.org/10.1038/nm.2558

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