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

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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. Brain-specific 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 brain-specific 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.