title: Comparative Mitochondrial-Based Protective Effects of Resveratrol and Nicotinamide in Huntington's Disease Models.
abstract: 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.
authors: CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504, Coimbra, Portugal.|Faculty of Medicine, University of Coimbra, Coimbra, 3004-504, Portugal.
authors: Luana
authors: L
authors: Naia
authors: CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504, Coimbra, Portugal.|Institute for Interdisciplinary Research, University of Coimbra (IIIUC), Polo II, Coimbra, Portugal.
authors: Tatiana R
authors: TR
authors: Rosenstock
authors: CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504, Coimbra, Portugal.
authors: Ana M
authors: AM
authors: Oliveira
authors: CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504, Coimbra, Portugal.
authors: Sofia I
authors: SI
authors: Oliveira-Sousa
authors: CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504, Coimbra, Portugal.|Institute for Interdisciplinary Research, University of Coimbra (IIIUC), Polo II, Coimbra, Portugal.
authors: Gladys L
authors: GL
authors: Caldeira
authors: CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504, Coimbra, Portugal.
authors: Catarina
authors: C
authors: Carmo
authors: CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504, Coimbra, Portugal.|Faculty of Medicine, University of Coimbra, Coimbra, 3004-504, Portugal.|Institute for Interdisciplinary Research, University of Coimbra (IIIUC), Polo II, Coimbra, Portugal.
authors: Mário N
authors: MN
authors: Laço
authors: Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
authors: Michael R
authors: MR
authors: Hayden
authors: CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504, Coimbra, Portugal.|Faculty of Medicine, University of Coimbra, Coimbra, 3004-504, Portugal.
authors: Catarina R
authors: CR
authors: Oliveira
authors: CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504, Coimbra, Portugal. a.cristina.rego@gmail.com.|Faculty of Medicine, University of Coimbra, Coimbra, 3004-504, Portugal. a.cristina.rego@gmail.com.
authors: A Cristina
authors: http://orcid.org/0000-0003-0700-3776
authors: AC
authors: Rego
mesh_terms: D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D006816:Huntington Disease / Q000235:genetics*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects*; D008822:Mice, Transgenic; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009536:Niacinamide / Q000494:pharmacology*; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology*
chemical_list: D004272:DNA, Mitochondrial; D013267:Stilbenes; D009536:Niacinamide; D000077185:Resveratrol
keywords: Huntington’s disease; Lysine (de)acetylation; Mitochondria; Nicotinamide; Resveratrol; Sirtuins