Article

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

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.

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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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    • "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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