title: Polyglutamine Tract Expansion Increases S-Nitrosylation of Huntingtin and Ataxin-1.
abstract: Expansion of the polyglutamine (polyQ) tract in the huntingtin (Htt) protein causes Huntington's disease (HD), a fatal inherited movement disorder linked to neurodegeneration in the striatum and cortex. S-nitrosylation and S-acylation of cysteine residues regulate many functions of cytosolic proteins. We therefore used a resin-assisted capture approach to identify these modifications in Htt. In contrast to many proteins that have only a single S-nitrosylation or S-acylation site, we identified sites along much of the length of Htt. Moreover, analysis of cells expressing full-length Htt or a large N-terminal fragment of Htt shows that polyQ expansion strongly increases Htt S-nitrosylation. This effect appears to be general since it is also observed in Ataxin-1, which causes spinocerebellar ataxia type 1 (SCA1) when its polyQ tract is expanded. Overexpression of nitric oxide synthase increases the S-nitrosylation of normal Htt and the frequency of conspicuous juxtanuclear inclusions of Htt N-terminal fragments in transfected cells. Taken together with the evidence that S-nitrosylation of Htt is widespread and parallels polyQ expansion, these subcellular changes show that S-nitrosylation affects the biology of this protein in vivo.
authors.affiliation: Cell Biology Program, Department of Molecular Biology and Microbiology, Case Western Reserve University, Cleveland, OH, 44106, United States of America.
authors.forename: Chun-Lun
authors.initials: CL
authors.lastname: Ni
authors.affiliation: Institute for Transformative Molecular Medicine, Case Western Reserve University, Cleveland, OH, 44106, United States of America.
authors.forename: Divya
authors.initials: D
authors.lastname: Seth
authors.affiliation: Institute for Transformative Molecular Medicine, Case Western Reserve University, Cleveland, OH, 44106, United States of America.
authors.forename: Fabio Vasconcelos
authors.initials: FV
authors.lastname: Fonseca
authors.affiliation: Center for Proteomics and Bioinformatics, Case Western Reserve University, Cleveland, OH, 44106, United States of America.
authors.forename: Liwen
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, OH, 44106, United States of America.
authors.forename: Tsan Sam
authors.initials: TS
authors.lastname: Xiao
authors.affiliation: Department of Biochemistry, School of Medicine, Case Western Reserve University, Cleveland, OH, 44106, United States of America.
authors.forename: Phillip
authors.initials: P
authors.lastname: Gruber
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, OH, 44106, United States of America.
authors.forename: Man-Sun
authors.initials: MS
authors.lastname: Sy
authors.affiliation: Institute for Transformative Molecular Medicine, Case Western Reserve University, Cleveland, OH, 44106, United States of America.
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Stamler
authors.affiliation: Cell Biology Program, Department of Molecular Biology and Microbiology, Case Western Reserve University, Cleveland, OH, 44106, United States of America.|Department of Pathology, Case Western Reserve University, Cleveland, OH, 44106, United States of America.
authors.forename: Alan M
authors.identifier: http://orcid.org/0000-0002-8094-3345
authors.initials: AM
authors.lastname: Tartakoff