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Sirt1 mediates neuroprotection from mutant huntingtin by activation of the TORC1 and CREB transcriptional pathway

Abstract

Sirt1, a NAD-dependent protein deacetylase, has emerged as a key regulator of mammalian transcription in response to cellular metabolic status and stress1. Here we show that Sirt1 has a neuroprotective role in models of Huntington's disease, an inherited neurodegenerative disorder caused by a glutamine repeat expansion in huntingtin protein (HTT)2. Brain-specific knockout of Sirt1 results in exacerbation of brain pathology in a mouse model of Huntington's disease, whereas overexpression of Sirt1 improves survival, neuropathology and the expression of brain-derived neurotrophic factor (BDNF) in Huntington's disease mice. We show that Sirt1 deacetylase activity directly targets neurons to mediate neuroprotection from mutant HTT. The neuroprotective effect of Sirt1 requires the presence of CREB-regulated transcription coactivator 1 (TORC1), a brain-specific modulator of CREB activity3. We show that under normal conditions, Sirt1 deacetylates and activates TORC1 by promoting its dephosphorylation and its interaction with CREB. We identified BDNF as a key target of Sirt1 and TORC1 transcriptional activity in both normal and Huntington's disease neurons. Mutant HTT interferes with the TORC1-CREB interaction to repress BDNF transcription, and Sirt1 rescues this defect in vitro and in vivo. These studies suggest a key role for Sirt1 in transcriptional networks in both the normal and Huntington's disease brain and offer an opportunity for therapeutic development.

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Figure 1: Ablation of neuronal Sirt1 exacerbates, and overexpression of Sirt1 ameliorates, Huntington's disease phenotypes in R6/2 mice.
Figure 2: The deaceylase activity of Sirt1 protects cortical neurons from mutant HTT toxicity.
Figure 3: Sirt1 deacetylates and activates TORC1.
Figure 4: Sirt1 rescues mutant-HTT–mediated interference with TORC1 activity.

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Acknowledgements

We thank M. Montminy (Peptide Biology Laboratories (PBL), Salk Institute) for the Flag-CREB, Flag-TORC1 and Flag-TORC1 S151A plasmids and for antibody to TORC1 (#6937, PBL, Salk Institute) and helpful discussions; M.E. Greenberg (Harvard Medical School) for the pIII(170)Luc plasmid15; T. Kouzarides (University of Cambridge) for Sirt1 and Sirt1 HY plasmids; Z. Wu (Novartis Institutes for Biomedical Research) for the TORC1 plasmid; M. Difiglia (Massachusetts General Hospital) for antibody to HTT (Ab1); E. Regulier (Novartis Institutes for Biomedical Research) for lentiviral vectors expressing HTTEx1-25Q, HTTEx1-72Q and Sirt1; and J.M. Park (Massachusetts General Hospital) for the lentiviral vector used for CREB knockdown. We also acknowledge C. Whitaker (Massachusetts Institute of Technology) for analysis of the microarray data. This work was supported by grant R01NS051303 from the US National Institutes of Health (D.K.); the Cure Huntington's Disease Initiative (CHDI), Hereditary Disease Foundation (HDF) (D.E.C.); US National Institutes of Health, Glenn Foundation for Medical Research (L.G.) and grants R01MH067880-08 and P41RR011823-15 from the US National Institutes of Health (J.R.Y.).

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Contributions

H.J. performed the experiments shown in Figures 2, 3, 4 and Supplementary Figures 4, 6 and 9–13. D.E.C. and A.S. performed the experiments shown in Figures 1a, 1e, 2c and 2d and Supplementary Figures 1 and 5. L.C. performed the experiments shown in Figure 1b–h and Supplementary Figures 13 and 14. J.R.M. helped with the experiments shown in Figure 4f. J.N.S. and J.R.Y. performed the experiments shown in Supplementary Figure 7. L.B. performed the experiments shown in Supplementary Figure 2. L.P.G. and D.K. provided the conceptual framework for the study and discussed the results. D.K. and H.J. wrote the paper.

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Correspondence to Dimitri Krainc.

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L.P.G. is a member of the Scientific Advisory Board of Sirtris, GlaxoSmithKline.

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Supplementary Figures 1–14 and Supplementary Methods (PDF 1220 kb)

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Jeong, H., Cohen, D., Cui, L. et al. Sirt1 mediates neuroprotection from mutant huntingtin by activation of the TORC1 and CREB transcriptional pathway. Nat Med 18, 159–165 (2012). https://doi.org/10.1038/nm.2559

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