title: Analysis of oxidative events induced by expanded polyglutamine huntingtin exon 1 that are differentially restored by expression of heat shock proteins or treatment with an antioxidant.
abstract: We recently reported that the transient expression of polyglutamine tracts of various size in exon 1 of the huntingtin polypeptide (httEx1) generated abnormally high levels of intracellular reactive oxygen species that directly contributed to cell death. Here, we compared the protection generated by heat shock proteins to that provided by the antioxidant agent N-acetyl-L-cysteine. In cells expressing httEx1 with 72 glutamine repeats (httEx1-72Q), the overexpression of Hsp27 or Hsp70 plus Hdj-1(Hsp40) or treatment of the cells with N-acetyl-L-cysteine inhibited not only mitochondrial membrane potential disruption but also the increase in reactive oxygen species, nitric oxide and protein oxidation. However, only heat shock proteins and not N-acetyl-L-cysteine reduced the size of the inclusion bodies formed by httEx1-72Q. In cells expressing httEx1 polypeptide with 103 glutamine repeats (httEx1-103Q), heat shock proteins neither decreased oxidative damage nor reduced the size of the inclusions. In contrast, N-acetyl-L-cysteine still efficiently decreased the oxidative damage induced by httEx1-103Q polypeptide without altering the inclusions. N-Acetyl-L-cysteine was inactive with regard to proteasome inhibition, whereas heat shock proteins partially restored the caspase-like activity of this protease. These observations suggest some relationships between the presence of inclusion bodies and the oxidative damage induced by httEx1-polyQ.
authors.affiliation: Laboratoire Stress Oxydant, Chaperons et Apoptose, Centre de Génétique Moléculaire et Cellulaire, Université Claude Bernard Lyon-1, Villeurbanne, France.
authors.forename: Wance J J
authors.initials: WJ
authors.lastname: Firdaus
authors.forename: Andreas
authors.initials: A
authors.lastname: Wyttenbach
authors.forename: Chantal
authors.initials: C
authors.lastname: Diaz-Latoud
authors.forename: R W
authors.initials: RW
authors.lastname: Currie
authors.forename: André-Patrick
authors.initials: AP
authors.lastname: Arrigo
mesh_terms: D000111:Acetylcysteine / Q000737:chemistry; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D019556:COS Cells; D002522:Chlorocebus aethiops; D005091:Exons; D005973:Glutamine / Q000737:chemistry; D055551:HSP27 Heat-Shock Proteins; D050956:HSP40 Heat-Shock Proteins / Q000737:chemistry; D006360:Heat-Shock Proteins / Q000737:chemistry*; D000071058:Huntingtin Protein; D018832:Molecular Chaperones; D009363:Neoplasm Proteins / Q000737:chemistry; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000235:genetics*; D009569:Nitric Oxide / Q000737:chemistry / Q000378:metabolism; D009687:Nuclear Proteins / Q000737:chemistry* / Q000235:genetics*; D018384:Oxidative Stress; D010447:Peptide Hydrolases / Q000737:chemistry; D010455:Peptides / Q000737:chemistry; D017382:Reactive Oxygen Species
chemical_list: D000975:Antioxidants; C494647:DNAJB1 protein, human; D055551:HSP27 Heat-Shock Proteins; D050956:HSP40 Heat-Shock Proteins; C057725:HSPB1 protein, human; C086055:HTT protein, human; D006360:Heat-Shock Proteins; D000071058:Huntingtin Protein; D018832:Molecular Chaperones; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; D017382:Reactive Oxygen Species; D005973:Glutamine; C097188:polyglutamine; D009569:Nitric Oxide; D010447:Peptide Hydrolases; D000111:Acetylcysteine