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Neuroprotective role of Sirt1 in mammalian models of Huntington's disease through activation of multiple Sirt1 targets

Nature Medicine volume 18, pages 153–158 (2012)Cite this article

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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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Figure 1: Sirt1 improves the motor function and attenuates brain atrophy in N171-82Q Huntington's disease mice and in BACHD mice.
Figure 2: Sirt1 preserves DARPP32 concentrations in the striatum, restores BDNF concentration and facilitates TrkB activation in Huntington's disease models.
Figure 3: Ablation of endogenous Sirt1 exacerbates mutant HTT toxicity, and the deacetylase activity of Sirt1 is required for its neuroprotection in a cell model of Huntington's disease.
Figure 4: Sirt1 counteracts mutant-HTT–induced hyperacetylation of Foxo3a and p53 and protects cells against mutant-HTT–mediated energy deficits in both mouse and cell models of 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.).

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Author notes

  1. Mali Jiang and Jiawei Wang: These authors contributed equally to this work.

Authors and 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. Department of Chemistry and Biochemistry, Natural Products Discovery Group, 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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  1. Mali Jiang
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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.

Corresponding author

Correspondence to Wenzhen Duan.

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The authors declare no competing financial interests.

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Jiang, M., Wang, J., Fu, J. et al. Neuroprotective role of Sirt1 in mammalian models of Huntington's disease through activation of multiple Sirt1 targets. Nat Med 18, 153–158 (2012). https://doi.org/10.1038/nm.2558

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