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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    • "The CNS and its control of lipidmetabolism has identified hypothalamic NPY with evidence that NPY has effects onY1 receptors to promote hepatic lipoprotein secretion to promote VLDL secretionvia the sympathetic nervous system[104][105]and on Y2 receptors to promote feeding. Sirt 1 regulation of BDNF[108]has been shown (Figure 4) and associated with altered NPY levels in the brain[109][110]and several studies have indicated its involvement in neuronal plasticity, behaviour, appetite control andbody weight regulation. BDNF is involved in the regulation of food intake and the levels of BDNF controlled by high fat diets. "

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    • "Whole-body overexpression of SIRT1 does not appear to extend life span in mice, even though it improves some metabolic parameters that may be associated with health span (Bordone et al. 2007). Several different promoters, including a variety of tissue-and cell-type-specific drivers, have also failed to show increased life span from SIRT1 overexpression in mice, although in some cases improved health measures were detected, similar to whole body overexpression (Alcendor et al. 2007; Herranz et al. 2010; Jeong et al. 2012). Recently, a mouse overexpressing SIRT1 specifically in the hypothalamus (BRASTO mice— brain-specific SIRT1 overexpressing) was reported to be both long-lived and have improved health span, suggesting that SIRT1 activity in the brain may be particularly important for healthy aging in mice (Satoh et al. 2013). "
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    ABSTRACT: The mechanisms underlying biological aging have been extensively studied in the past 20 years with the avail of mainly four model organisms: the budding yeast Saccharomyces cerevisiae, the nematode Caenorhabditis elegans, the fruitfly Drosophila melanogaster, and the domestic mouse Mus musculus. Extensive research in these four model organisms has identified a few conserved genetic pathways that affect longevity as well as metabolism and development. Here, we review how the mechanistic target of rapamycin (mTOR), sirtuins, adenosine monophosphate-activated protein kinase (AMPK), growth hormone/insulin-like growth factor 1 (IGF-1), and mitochondrial stress-signaling pathways influence aging and life span in the aforementioned models and their possible implications for delaying aging in humans. We also draw some connections between these biochemical pathways and comment on what new developments aging research will likely bring in the near future. © 2015 Cold Spring Harbor Laboratory Press; all rights reserved.
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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.
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