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

Department of Neurology, Massachusetts General Hospital, MassGeneral Institute for Neurodegenerative Disease, Harvard Medical School, Charlestown, Massachusetts, USA.
Nature medicine (Impact Factor: 27.36). 12/2011; 18(1):159-65. DOI: 10.1038/nm.2559
Source: PubMed

ABSTRACT Sirt1, a NAD-dependent protein deacetylase, has emerged as a key regulator of mammalian transcription in response to cellular metabolic status and stress. 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). 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 activity. 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.

Download full-text


Available from: Jeffrey N Savas, Sep 16, 2014
29 Reads
  • Source
    • ". Previous studies suggested that TORC1 (CREBregulated transcription coactivator 1) activated CREB-regulated transcription by promoting the recruitment of transcriptional co-activators to BDNF promoter. Authors showed that mHTT may affect TORC1–CREB interaction, thus repressing BDNF transcription; contrariwise, SIRT1 deacetylates and activates TORC1 by promoting its interaction with CREB [47] (Fig. 1). If we consider SIRT1 as a factor involved in chromatin regulation, constitutive SIRT1 OE may not always be beneficial. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Sirtuins are a conserved family of NAD(+)-dependent class III lysine deacetylases, known to regulate longevity. In mammals, the sirtuin family has seven members (SIRT1-7), which vary in enzymatic activity, subcellular distribution and targets. Pharmacological and genetic modulation of SIRTs has been widely spread as a promising approach to slow aging and neurodegenerative processes. Huntington's disease (HD) is a neurodegenerative disorder linked to expression of polyglutamine-expanded huntingtin (HTT) protein for which there is still no disease-reversing treatment. Studies in different animal models provide convincing evidence that SIRT1 protects both cellular and animal models from mutant HTT toxicity, however controversial results were recently reported. Indeed, as a consequence of a variety of SIRT-activation pathways, either activation or inhibition of a specific SIRT appears to be neuroprotective. Therefore, this review summarizes the recent progress and knowledge in sirtuins (particularly SIRT1-3) and their implications for HD treatment. Copyright © 2015. Published by Elsevier B.V.
    Biochimica et Biophysica Acta 07/2015; DOI:10.1016/j.bbadis.2015.07.003 · 4.66 Impact Factor
  • Source
    • "TORC1/CREB* Neuroprotective role in the pathogenesis of Huntington's disease. Jeong et al. (37); 2011. Duan (38); 2013. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Environmental conditions and increased physical activity during scuba diving are followed by increased production of free radicals and disturbed redox balance. Redox balance disorder is associated with damage of cellular components, changes of cellular signaling pathways and alterations of gene expression. Oxidative stress leads to increased expression of sirtuins (SIRTs), molecules which play an important role in the antioxidant defense, due to their sensitivity to the changes in the redox status and their ability to regulate redox homeostasis. These facts make SIRTs interesting to be considered as molecules affected by scuba diving and in that sense, as potential biomarkers of oxidative status or possible drug targets in reduction of reactive oxygen species (ROS) accumulation. In addition, SIRTs effects through currently known targets make them intriguing molecules which can act positively on health in general and whose expression can be induced by scuba diving. A demanding physical activity, as well as other circumstances present in scuba diving, has the greatest load on the cardiovascular function (CV). The mechanisms of CV response during scuba diving are still unclear, but diving-induced oxidative stress and the increase in SIRTs expression could be an important factor in CV adaptation. This review summarizes current knowledge on scuba diving-induced oxidative and CV stress and describes the important roles of SIRTs in the (patho)physiological processes caused by the redox balance disorder.
    Biochemia Medica 06/2014; 24(2):235-47. DOI:10.11613/BM.2014.026 · 2.67 Impact Factor
  • Source
    • "Strikingly, the sirtuin family members seem to be intimately linked to pathogenesis in HD, since the NAD+-dependent deacetylase activity of SIRT1 is also involved in the regulation of transcription in HD. SIRT1 is a nuclear protein that normally controls CREB phosphorylation levels via TORC1 (Regulated transcription co-activator 1 (TORC1) activity (47, 48). By interacting with SIRT1, Exp-Htt inhibits its deacetylase activity, and causes hyperacetylation of TORC1. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Huntington’s Disease (HD) is a genetic neurodegenerative disease caused by a CAG expansion in the gene encoding Huntingtin (Htt). It is characterized by chorea, cognitive and psychiatric disorders. The most affected brain region is the striatum, and the clinical symptoms are directly correlated to the rate of striatal degeneration. The wild-type Htt is a ubiquitous protein and its deletion is lethal. Mutated (expanded) Htt produces excitotoxicity, mitochondrial dysfunctions, axonal transport deficit, altered proteasome activity, and gene dysregulation. Transcriptional dysregulation occurs at early neuropathological stages in HD patients. Multiple genes are dysregulated, with overlaps of altered transcripts between mouse models of HD and patient brains. Nuclear localization of Exp-Htt interferes with transcription factors, co-activators and proteins of the transcriptional machinery. Another key mechanism described so far, is an alteration of cytoplasmic retention of the transcriptional repressor REST, which is normally associated with wild-type Htt. As such, Exp-Htt causes alteration of transcription of multiple genes involved in neuronal survival, plasticity, signaling and mitochondrial biogenesis and respiration. Besides these transcriptional dysregulations, Exp-Htt affects the chromatin structure through altered post-translational modifications (PTM) of histones and methylation of DNA. Multiple alterations of histone PTM are described, including acetylation, methylation, ubiquitylation, polyamination and phosphorylation. Exp-Htt also affects the expression and regulation of non-coding microRNAs. First multiple neural microRNAs are controlled by REST, and dysregulated in HD, with concomitant de-repression of downstream mRNA targets. Second, Exp-Htt protein or RNA may also play a major role in the processing of miRNAs and hence pathogenesis. These pleiotropic effects of Exp-Htt on gene expression may represent seminal deleterious effects on the pathology.
    Frontiers in Neurology 10/2013; 4:127. DOI:10.3389/fneur.2013.00127
Show more