title: Oxidative stimuli affect polyglutamine aggregation and cell death in human mutant ataxin-1-expressing cells.
abstract: Spinocerebellar ataxia 1 (SCA1), one of the inherited polyglutamine neurodegenerative diseases, is associated with intracellular aggregates. However, the process of aggregate formation and the factors that influence aggregation remain unclear. Here, we show that oxidative stimuli and alteration of the cellular redox state significantly affect aggregation and cell death in cells expressing mutant ataxin-1, the SCA gene product. Treatment of cells with buthionine sulfoximine, hydrogen peroxide or t-butylhydroperoxide increased the formation of mutant ataxin-1 aggregates, but treatment with the anti-oxidant, N-acetylcysteine (NAC), decreased aggregate formation. Oxidative damage of mutant ataxin-1 protein increased its recruitment in nuclear aggregates and increased cell death. However, NAC treatments reduced cell death and the number of cells with abnormal morphology. Our results might give insight into the mechanism whereby polyglutamine proteins aggregate and suggest that treatment of appropriate antioxidant reagents might prevent progression of SCA1 and other polyglutamine diseases.
authors.affiliation: Laboratory of Molecular Genetics, Graduate School of Biotechnology, Korea University, Seoul 136-701, South Korea.
authors.forename: Sung-Jo
authors.initials: SJ
authors.lastname: Kim
authors.forename: Tae-soo
authors.initials: TS
authors.lastname: Kim
authors.forename: Sunghoi
authors.initials: S
authors.lastname: Hong
authors.forename: Hyangshuk
authors.initials: H
authors.lastname: Rhim
authors.forename: Ick Young
authors.initials: IY
authors.lastname: Kim
authors.forename: Seongman
authors.initials: S
authors.lastname: Kang
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D000067696:Ataxin-1; D000067528:Ataxins; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D002449:Cell Aggregation / Q000502:physiology*; D016923:Cell Death / Q000502:physiology*; D005455:Fluorescent Antibody Technique / Q000379:methods; D016166:Free Radical Scavengers / Q000494:pharmacology; D049452:Green Fluorescent Proteins; D006367:HeLa Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D015151:Immunoblotting / Q000379:methods; D008164:Luminescent Proteins / Q000378:metabolism; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D010455:Peptides / Q000276:immunology / Q000378:metabolism*; D011837:Radiation-Protective Agents / Q000494:pharmacology; D051381:Rats; D013997:Time Factors; D014162:Transfection; D020122:tert-Butylhydroperoxide / Q000494:pharmacology
chemical_list: C000593749:ATXN1 protein, human; D000067696:Ataxin-1; D000067528:Ataxins; C000593751:Atxn1 protein, rat; D016166:Free Radical Scavengers; D008164:Luminescent Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D016877:Oxidants; D010455:Peptides; D011837:Radiation-Protective Agents; D049452:Green Fluorescent Proteins; C097188:polyglutamine; D019328:Buthionine Sulfoximine; D020122:tert-Butylhydroperoxide; D006861:Hydrogen Peroxide; D000111:Acetylcysteine