Open AccessPolyglutamine Tract Expansion Increases S-Nitrosylation of Huntingtin and Ataxin-1
Author(s) -
ChunLun Ni,
Divya Seth,
Fabiana Valéria da Fonseca,
Liwen Wang,
Tsan Sam Xiao,
Phillip Gruber,
ManSun Sy,
Jonathan S. Stamler,
Alan M. Tartakoff
Publication year - 2016
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0163359
Subject(s) - s nitrosylation , huntingtin , neurodegeneration , huntingtin protein , polyglutamine tract , microbiology and biotechnology , spinocerebellar ataxia , trinucleotide repeat expansion , biology , huntington's disease , chemistry , cysteine , ataxia , genetics , biochemistry , neuroscience , pathology , medicine , allele , disease , gene , mutant , enzyme
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 .