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

Jeong, Hyeong-Chai; Cohen, David S.; Cui, Libin; Supinski, Andrea; Savas, Jeffrey N.; Mazzulli, Joseph R.; Yates, John R.; Bordone, Laura; Guarente, Leonard; Krainc, Dimitri

doi:10.1038/nm.2559

Cited by 325 publications

(284 citation statements)

References 41 publications

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“…1 Thereby, a decrease in SIRT1 expression has been detected in AD, 40 PD 41 and HD 42 patient brain samples, which is correlated with decreased PGC-1α activity. [43][44][45] Indeed, the promotion of SIRT1 activity either genetically or pharmacologically with RSV, has been shown to combat several pathological hallmarks of neurodegeneration in a variety of models for AD, [46][47][48][49] and HD, 51,52 supporting the neuroprotective notion of SIRT1 activation. However, recent studies have shown diametrically opposed results, indicating that selective SIRT1 inhibitors offer neuroprotection in cells and animal models of HD, 8 or that overexpression of PGC-1α exacerbates β-amyloid and tau deposition in an AD mouse model.…”

Section: Discussionmentioning

confidence: 94%

Activation of sirtuin 1 as therapy for the peroxisomal disease adrenoleukodystrophy

et al. 2015

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Oxidative stress and mitochondrial failure are prominent factors in the axonal degeneration process. In this study, we demonstrate that sirtuin 1 (SIRT1), a key regulator of the mitochondrial function, is impaired in the axonopathy and peroxisomal disease X-linked adrenoleukodystrophy (X-ALD). We have restored SIRT1 activity using a dual strategy of resveratrol treatment or by the moderate transgenic overexpression of SIRT1 in a X-ALD mouse model. Both strategies normalized redox homeostasis, mitochondrial respiration, bioenergetic failure, axonal degeneration and associated locomotor disabilities in the X-ALD mice. These results indicate that the reactivation of SIRT1 may be a valuable strategy to treat X-ALD and other axonopathies in which the control of redox and energetic homeostasis is impaired. Cell Death and Differentiation (2015) 22, 1742-1753 doi:10.1038/cdd.2015; published online 27 March 2015Sirtuins are highly conserved NAD + -dependent deacetylases with a critical impact on metabolic adaptive responses. In mammals, among the seven members of the sirtuin family (SIRT1-SIRT7), SIRT1 has been the most extensively characterized. 1 SIRT1 promotes the generation of new mitochondria through the activation of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α), which orchestrates the mitochondrial biogenesis program through the transcriptional activation of nuclear respiratory factors (NRF-1 and NRF-2) and mitochondrial transcription factor A (TFAM). 2 SIRT1 activity is finely regulated not only by gene expression and protein levels but also by posttranslational modifications, its oligomeric status, the interaction with the DBC1 and AROS proteins, and the levels of NAD + /NADH/NAM. 3 In addition, SIRT1 activity is modulated by several synthetic or natural molecules such as the polyphenol resveratrol (3,4',5-trihydroxystilbene: RSV). 4 The activation of SIRT1 by transgenic overexpression or pharmacologically with RSV has been shown to prevent the pathology in diseases commonly associated with mitochondrial dysfunction such as the metabolic syndrome and neurodegenerative disorders, 1,5,6 albeit recent findings cast doubts on the universal validity of the results. 7,8 Although prominent axonal pathology often precedes cell body loss in many neurodegenerative diseases, 9 the potential of SIRT1 activation in axonal degeneration has not been addressed in depth. In this work, we take advantage of the cellular and animal models of the rare monogenic neurodegenerative disease named X-linked adrenoleukodystrophy (X-ALD, (McKusick No.300100)) to evaluate the impact of SIRT1 function on axonal degeneration. X-ALD is the most prevalent peroxisomal disorder (minimum incidence 1:17 000 newborns), characterized by brain inflammatory demyelination and/or axonopathy of long tracts in spinal cords, adrenal insufficiency and a pathognomonic accumulation of very longchain fatty acids (VLCFA) in plasma and tissues, in particular hexacosanoic acid (C26:0). 10,11 The disease phenotypes range from adrenal ...

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Section: Discussionmentioning

confidence: 94%

Activation of sirtuin 1 as therapy for the peroxisomal disease adrenoleukodystrophy

et al. 2015

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“…We favor this model because the CBD N terminus features several invariant basic residues (Arg20, Lys21, and Lys25 in CRTC2) that could serve to both orient the helix and enhance the stability of this complex by engaging the phosphate groups in DNA in electrostatic interactions. In support of this idea, acetylation of lysine residues in the CBD or their mutation to glutamine has been implicated in diminishing CRTC-CREB interactions (20). The nonspecific interactions with DNA might explain why CRTCs engage CREB bound to diverse CREs with similar affinities.…”

Section: Discussionmentioning

confidence: 97%

Mechanism of CREB recognition and coactivation by the CREB-regulated transcriptional coactivator CRTC2

Luo

Viste

Urday-Zaa

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Basic leucine zipper (bZip) transcription factors regulate cellular gene expression in response to a variety of extracellular signals and nutrient cues. Although the bZip domain is widely known to play significant roles in DNA binding and dimerization, recent studies point to an additional role for this motif in the recruitment of the transcriptional apparatus. For example, the cAMP response element binding protein (CREB)-regulated transcriptional coactivator (CRTC) family of transcriptional coactivators has been proposed to promote the expression of calcium and cAMP responsive genes, by binding to the CREB bZip in response to extracellular signals. Here we show that the CREB-binding domain (CBD) of CRTC2 folds into a single isolated 28-residue helix that seems to be critical for its interaction with the CREB bZip. The interaction is of micromolar affinity on palindromic and variant half-site cAMP response elements (CREs). The CBD and CREB assemble on the CRE with 2:2:1 stoichiometry, consistent with the presence of one CRTC binding site on each CREB monomer. Indeed, the CBD helix and the solvent-exposed residues in the dimeric CREB bZip coiled-coil form an extended protein-protein interface. Because mutation of relevant bZip residues in this interface disrupts the CRTC interaction without affecting DNA binding, our results illustrate that distinct DNA binding and transactivation functions are encoded within the structural constraints of a canonical bZip domain.transcription regulation | cellular signaling | protein-protein interaction

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“…Silent mating type information regulation 2 homolog 1 (Sirt1) is an emerging focus in neuroprotection in both the central nervous system (8,9) and peripheral nervous system (10)(11)(12). In our previous study, overexpression of Sirt1 promoted epithelial wound healing in diabetic corneas (13,14).…”

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confidence: 98%

microRNA-182 Mediates Sirt1-Induced Diabetic Corneal Nerve Regeneration

Wang

Zhao

et al. 2016

Diabetes

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Sensory neurons are particularly susceptible to neuronal damage in diabetes, and silent mating type information regulation 2 homolog 1 (Sirt1) has been recently identified as a key gene in neuroprotection and wound healing. We found that the expression of Sirt1 was downregulated in trigeminal sensory neurons of diabetic mice. A microRNA microarray analysis identified microRNA-182 (miR-182) as a Sirt1 downstream effector, and the expression level of miR-182 was increased by Sirt1 overexpression in trigeminal neurons; Sirt1 bound to the promoter of miR-182 and regulated its transcription. We also revealed that miR-182 enhanced neurite outgrowth in isolated trigeminal sensory neurons and overcame the detrimental effects of hyperglycemia by stimulating corneal nerve regeneration by decreasing the expression of one of its target genes, NOX4. Furthermore, the effects of miR-182 on corneal nerve regeneration are associated with a functional recovery of corneal sensation in hyperglycemic conditions. These data demonstrate that miR-182 is a key regulator in diabetic corneal nerve regeneration through targeting NOX4, suggesting that miR-182 might be a potential target for the treatment of diabetic sensory nerve regeneration and diabetic keratopathy.

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

Cited by 325 publications

References 41 publications

Activation of sirtuin 1 as therapy for the peroxisomal disease adrenoleukodystrophy

Activation of sirtuin 1 as therapy for the peroxisomal disease adrenoleukodystrophy

Mechanism of CREB recognition and coactivation by the CREB-regulated transcriptional coactivator CRTC2

microRNA-182 Mediates Sirt1-Induced Diabetic Corneal Nerve Regeneration

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