Rosenstock T.R, Naia L, Oliveira-Sousa S.I, Oliveira A, Caldeira G.L, Laço M.N, Hayden M.Rand Rego A.C
Accepted Abstracts: J Neurol Neurophysiol
Mammalian sirtuins are a conserved family of class III NAD+-dependent deacetylases, which have been postulated to be beneficial for targeting mitochondrial abnormalities. In this respect, Huntington?s disease (HD) has been commonly linked to mitochondrial dysfunction as one of the main pathological mechanisms. We hypothesized that modulation of sirtuins might be beneficial in HD. We tested how changes in acetylation status, induced by resveratrol (RESV) versus nicotinamide (NAM), counteract mitochondrial dysfunction in HD cell models expressing full-length human mutant huntingtin. Moreover, we analyzed the effect of RESV and NAM in in vivo HD models. In in vivo study, 1 mg/kg/day RESV and 250 mg/kg/day NAM were administered to 9 month-old YAC128 versus wild-type (WT) mice during 28 days. RESV slightly increased the latency to fall off in rotarod test; RESV and NAM greatly increased histone acetylation in both YAC128 and WT striatal and cortical samples. RESV also increased the expression of mitochondrial-encoded genes in YAC128 cortical samples. Using striatal and cortical neurons isolated from YAC128 transgenic mice embryos and HD human lymphoblast cell lines, we observed a slight decrease in histone acetylation with RESV and increased histone acetylation with NAM. Both HD cell models exhibited a decrease in Sirt3 levels, accompanied by a deregulation in mitochondrial respiration and membrane potential. Interestingly, both RESV and NAM were able to restore most of the evaluated parameters, providing a positive add on mitochondrial function in HD. Data suggest that RESV and NAM may be able to modulate protein acetylation and mitochondrial function in HD.
