title: Sir2 is induced by oxidative stress in a yeast model of Huntington disease and its activation reduces protein aggregation.
abstract: Huntington disease (HD) is a neurodegenerative disorder caused by expansion of CAG trinucleotide repeats, leading to an elongated polyglutamine sequence (polyQ) in the huntingtin protein. Misfolding of mutant polyQ proteins with expanded tracts results in aggregation, causing cytotoxicity. Oxidative stress in HD has been documented in humans as important to disease progression. Using yeast cells as a model of HD, we report that when grown at high glucose concentration, cells expressing mutant polyQ do not show apparent oxidative stress. At higher cell densities, when glucose becomes limiting and cells are metabolically shifting from fermentation to respiration, protein oxidation and catalase activity increases in relation to the length of the polyQ tract. Oxidative stress, either endogenous as a result of mutant polyQ expression or exogenously generated, increases Sir2 levels. Δ sir2 cells expressing expanded polyQ lengths show signs of oxidative stress even at the early exponential phase. In a wild-type background, isonicotinamide, a Sir2 activator, decreases mutant polyQ aggregation and the stress generated by expanded polyQ. Taken together, these results describe mutant polyQ proteins as being more toxic in respiring cells, causing oxidative stress and an increase in Sir2 levels. Activation of Sir2 would play a protective role against this toxicity.
authors.affiliation: Departament de Ciències Mèdiques Bàsiques, IRBLLeida, Universitat de Lleida, Facultat de Medicina, Spain.
authors.forename: M Alba
authors.initials: MA
authors.lastname: Sorolla
authors.forename: Clara
authors.initials: C
authors.lastname: Nierga
authors.forename: M José
authors.initials: MJ
authors.lastname: Rodríguez-Colman
authors.forename: Gemma
authors.initials: G
authors.lastname: Reverter-Branchat
authors.forename: Alicia
authors.initials: A
authors.lastname: Arenas
authors.forename: Jordi
authors.initials: J
authors.lastname: Tamarit
authors.forename: Joaquim
authors.initials: J
authors.lastname: Ros
authors.forename: Elisa
authors.initials: E
authors.lastname: Cabiscol
mesh_terms: D006801:Humans; D006816:Huntington Disease / Q000235:genetics* / Q000378:metabolism*; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D009536:Niacinamide / Q000494:pharmacology; D018384:Oxidative Stress; D010455:Peptides / Q000235:genetics* / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics* / Q000378:metabolism*; D038281:Silent Information Regulator Proteins, Saccharomyces cerevisiae / Q000378:metabolism*; D056565:Sirtuin 2 / Q000378:metabolism*
chemical_list: D050505:Mutant Proteins; D010455:Peptides; D038281:Silent Information Regulator Proteins, Saccharomyces cerevisiae; D009536:Niacinamide; C097188:polyglutamine; C027681:isonicotinamide; C087778:SIR2 protein, S cerevisiae; D056565:Sirtuin 2