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.
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Compliance with Ethical Standards
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.
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