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

Sirt1, an NAD-dependent protein deacetylase has emerged as important regulator of mammalian transcription in response to cellular metabolic status and stress1. Here we demonstrate that Sirt1 plays a neuroprotective role in models of Huntington’s disease (HD), an inherited neurodegenerative disorder caused by a glutamine repeat expansion in huntingtin protein2. Brainspecific knockout of Sirt1 results in exacerbation of brain pathology in HD mice, whereas overexpression of Sirt1 improves survival, neuropathology and BDNF expression in HD mice. We show that Sirt1 deacetylase activity directly targets neurons to mediate neuroprotection from mutant huntingtin. The neuroprotective effect of Sirt1 requires the presence of TORC1, a brainspecific modulator of CREB activity3. We show that under normal conditions Sirt1 deacetylates and activates TORC1 by promoting its dephoshorylation and interaction with CREB. We identified BDNF as an important target of Sirt1 and TORC1 transcriptional activity in normal and HD neurons. Mutant huntingtin 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 of Sirt1 in transcriptional networks in normal and HD brain and offer an opportunity for therapeutic development. Recent evidence suggests that Sirt1, a member of sirtuin family that has been implicated in aging and metabolism, plays a protective role in neurodegenerative disorders1. However, the exact nature of normal Sirt1 function in mammalian brain has yet to be ascertained. To +To whom correspondence should be addressed: Dr. Dimitri Krainc, MassGeneral Institute for Neurodegenerative Disease, 114 16th Street, Room 2008, Charlestown, MA 02129, Fax: 617-724-1480, [email protected], Dr. Leonard Guarente, Paul F. Glenn Laboratory, Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, Fax: (617) 253-8699, [email protected]. *These authors contributed equally to this work AUTHOR CONTRIBUTIONS H.J performed experiments in figures 2, 3, 4, S4, S6, S9, S9, S10, S11, S12, S13; D.C and A.S. performed experiments in figures 1a, 1e, 2c, 2d, S1, S5; L.C performed experiments in figures 1b-h, S13, S14; J.R.M helped with experiments in figure 4f; J.N.S and J.R.Y performed experiments in S7; L.B. performed experiments in S2; L.P.G and D.K provided conceptual framework and discussed the results; D.K. and H.J. wrote the paper. COMPETING FINANCIAL INTERESTS L. Guarente is a member of the Scientific Advisory Board of Sirtris/Glaxo Smith Kline. NIH Public Access Author Manuscript Nat Med. Author manuscript; available in PMC 2012 November 29. Published in final edited form as: Nat Med. ; 18(1): 159–165. doi:10.1038/nm.2559.