Sirtuin 1 (SIRT1) is a nicotinamide adenine dinucleotide (NAD+)-dependent lysine deacetylase that regulates longevity and enhances mitochondrial metabolism. Both activation and inhibition of SIRT1 were previously shown to ameliorate neuropathological mechanisms in Huntington’s disease (HD), a neurodegenerative disease that selectively affects the striatum and cortex and is commonly linked to mitochondrial dysfunction. Thus, in this study, we tested the influence of resveratrol (RESV, a SIRT1 activator) versus nicotinamide (NAM, a SIRT1 inhibitor) in counteracting mitochondrial dysfunction in HD models, namely striatal and cortical neurons isolated from YAC128 transgenic mice embryos, HD human lymphoblasts, and an in vivo HD model. HD cell models displayed a deregulation in mitochondrial membrane potential and respiration, implicating a decline in mitochondrial function. Further studies revealed decreased PGC-1α and TFAM protein levels, linked to mitochondrial DNA loss in HD lymphoblasts. Remarkably, RESV completely restored these parameters, while NAM increased NAD+ levels, providing a positive add on mitochondrial function in in vitro HD models. In general, RESV decreased while NAM increased H3 acetylation at lysine 9. In agreement with in vitro data, continuous RESV treatment for 28 days significantly improved motor coordination and learning and enhanced expression of mitochondrial-encoded electron transport chain genes in YAC128 mice. In contrast, high concentrations of NAM blocked mitochondrial-related transcription, worsening motor phenotype. Overall, data indicate that activation of deacetylase activity by RESV improved gene transcription associated to mitochondrial function in HD, which may partially control HD-related motor disturbances.
Animals’ maintenance and procedures were performed in accordance with the protocols approved by the Ethical Commission from the Faculty of Medicine, University of Coimbra (FMUC). Euthanasia by halothane or isoflurane anesthesia and decapitation was performed according to EU guideline 86/609/EEC and Annex II of Portuguese decree-law No. 113/2013.
This work was supported by “Fundo Europeu de Desenvolvimento Regional” (FEDER) funds through the “Programa Operacional Factores de Competitividade” (COMPETE), projects reference PEst-C/SAU/LA0001/2013–2014 and UID/NEU/04539/2013; and by national funds through “Fundação para a Ciência e a Tecnologia” (FCT), projects reference PTDC/SAU-FCF/108056/2008, EXPL/BIM-MEC/2220/2013, and Mantero Belard Neuroscience prize 2013, supported by Santa Casa da Misericórdia de Lisboa (SCML), Portugal. L.N. was supported by the FCT PhD fellowship SFRH/BD/86655/2012; T.R.R. and M.N.L. were supported by the FCT postdoctoral fellowships SFRH/BPD/44246/2008 and SFRH/BPD/91811/2012, respectively; and A.M.O. was supported by the FCT technician fellowship under the research project EXPL/BIM-MEC/2220/2013, cofinanced by Programa Operacional Potencial Humano (POPH), QREN, and European Union.
Conflict of Interest
The authors declare that they have no conflict of interest.
Silva AC, Almeida S, Laço M, et al. (2013) Mitochondrial respiratory chain complex activity and bioenergetic alterations in human platelets derived from pre-symptomatic and symptomatic huntington’s disease carriers. Mitochondrion 13:801–809. doi:10.1016/j.mito.2013.05.006CrossRefPubMedGoogle Scholar
Naia L, Ferreira IL, Cunha-Oliveira T, et al. (2015) Activation of IGF-1 and insulin signaling pathways ameliorate mitochondrial function and energy metabolism in Huntington’s disease human lymphoblasts. Mol Neurobiol 51:331–348. doi:10.1007/s12035-014-8735-4CrossRefPubMedGoogle Scholar
Jiang M, Wang J, Fu J, et al. (2012) Neuroprotective role of Sirt1 in mammalian models of Huntington’s disease through activation of multiple Sirt1 targets. Nat Med 18:153–158. doi:10.1038/nm.2558CrossRefGoogle Scholar
Naia L, Ribeiro M, Rodrigues J, et al. (2016) Insulin and IGF-1 regularize energy metabolites in neural cells expressing full-length mutant huntingtin. Neuropeptides:1–9. doi:10.1016/j.npep.2016.01.009
Hankes LV, Coenen HH, Rota E, et al. (1991) Effect of Huntington’s and Alzheimer’s diseases on the transport of nicotinic acid or nicotinamide across the human blood-brain barrier. AdvExpMedBiol 294:675–678Google Scholar
Panov AV, Gutekunst CA, Leavitt BR, et al. (2002) Early mitochondrial calcium defects in Huntington’s disease are a direct effect of polyglutamines. Nat Neurosci 5:731–736. doi:10.1038/nn884PubMedGoogle Scholar
Cunha-Oliveira T, Lusa I, Cristina A (2012) Consequences of mitochondrial dysfunction in Huntington’s disease and protection via phosphorylation pathways. Huntington’s Dis - Core Concepts Curr Adv. doi:10.5772/32728Google Scholar
Lopes costa A, Le bachelier C, Mathieu L, et al. (2014) Beneficial effects of resveratrol on respiratory chain defects in patients’ fibroblasts involve estrogen receptor and estrogen-related receptor alpha signaling. Hum Mol Genet 23:2106–2119. doi:10.1093/hmg/ddt603CrossRefPubMedGoogle Scholar
Bitterman KJ, Anderson RM, Cohen HY, et al. (2002) Inhibition of silencing and accelerated aging by nicotinamide, a putative negative regulator of yeast Sir2 and human SIRT1. J Biol Chem 277:45099–45107. doi:10.1074/jbc.M205670200CrossRefPubMedGoogle Scholar
Klaidman L, Morales M, Kem S, et al. (2003) Nicotinamide offers multiple protective mechanisms in stroke as a precursor for NAD+, as a PARP inhibitor and by partial restoration of mitochondrial function. Pharmacology 69:150–157. doi:10.1159/000072668CrossRefPubMedGoogle Scholar
Liu D, Gharavi R, Pitta M, et al. (2009) Nicotinamide prevents NAD+ depletion and protects neurons against excitotoxicity and cerebral ischemia: NAD+ consumption by sirt1 may endanger energetically compromised neurons. Neruomol Med 11:28–42. doi:10.1007/s12017-009-8058-1CrossRefGoogle Scholar