Jeong, H. et al. Sirt1 mediates neuroprotection from mutant huntingtin by activation of the TORC1 and CREB transcriptional pathway. Nature Med. 18, 159-165

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


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.

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Available from: Jeffrey N Savas, Sep 16, 2014
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    • "It has diverse functions in the brain including modulation of memory in rodents and flies (Zhou et al., 2006; Sekeres et al., 2012; Hirano et al., 2013; Nonaka et al., 2014), entrainment of circadian rhythms (Jagannath et al., 2013), neuroprotection during ischemia (Sasaki et al., 2011), and regulation of cocaine-induced plasticity (Hollander et al., 2010). Both Huntington's and Alzheimer's diseases have also been linked with CRTC1-mediated activation of CREB transcription of specific target genes (Jeong et al., 2012; Saura, 2012). We previously reported that CRTC1 undergoes activitydependent rapid translocation from distal dendrites to the nucleus during long-term plasticity of hippocampal neurons (Ch'ng et al., 2012). "
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    ABSTRACT: Previous studies have revealed a critical role for CREB-regulated transcriptional coactivator (CRTC1) in regulating neuronal gene expression during learning and memory. CRTC1 localizes to synapses but undergoes activity-dependent nuclear translocation to regulate the transcription of CREB target genes. Here we investigate the long-distance retrograde transport of CRTC1 in hippocampal neurons. We show that local elevations in calcium, triggered by activation of glutamate receptors and L-type voltage-gated calcium channels, initiate active, dynein-mediated retrograde transport of CRTC1 along microtubules. We identify a nuclear localization signal within CRTC1, and characterize three conserved serine residues whose dephosphorylation is required for nuclear import. Domain analysis reveals that the amino-terminal third of CRTC1 contains all of the signals required for regulated nucleocytoplasmic trafficking. We fuse this region to Dendra2 to generate a reporter construct and perform live-cell imaging coupled with local uncaging of glutamate and photoconversion to characterize the dynamics of stimulus-induced retrograde transport and nuclear accumulation.
    Frontiers in Molecular Neuroscience 09/2015; 8:48. DOI:10.3389/fnmol.2015.00048 · 4.08 Impact Factor
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    • ". 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. "
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    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
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    • "TORC1/CREB* Neuroprotective role in the pathogenesis of Huntington's disease. Jeong et al. (37); 2011. Duan (38); 2013. "
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    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
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