Polyglutamine Tract Expansion Increases S-Nitrosylation of Huntingtin and Ataxin-1

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 protein...

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Main Authors:	Ni, Chun-Lun, Seth, Divya, Fonseca, Fabio Vasconcelos, Wang, Liwen, Xiao, Tsan Sam, Gruber, Phillip, Sy, Man-Sun, Stamler, Jonathan S., Tartakoff, Alan M.
Format:	Online
Language:	English
Published:	Public Library of Science 2016
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5033456/

id	pubmed-5033456
recordtype	oai_dc
spelling	pubmed-50334562016-10-10 Polyglutamine Tract Expansion Increases S-Nitrosylation of Huntingtin and Ataxin-1 Ni, Chun-Lun Seth, Divya Fonseca, Fabio Vasconcelos Wang, Liwen Xiao, Tsan Sam Gruber, Phillip Sy, Man-Sun Stamler, Jonathan S. Tartakoff, Alan M. Research Article 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. Public Library of Science 2016-09-22 /pmc/articles/PMC5033456/ /pubmed/27658206 http://dx.doi.org/10.1371/journal.pone.0163359 Text en © 2016 Ni et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Ni, Chun-Lun Seth, Divya Fonseca, Fabio Vasconcelos Wang, Liwen Xiao, Tsan Sam Gruber, Phillip Sy, Man-Sun Stamler, Jonathan S. Tartakoff, Alan M.
spellingShingle	Ni, Chun-Lun Seth, Divya Fonseca, Fabio Vasconcelos Wang, Liwen Xiao, Tsan Sam Gruber, Phillip Sy, Man-Sun Stamler, Jonathan S. Tartakoff, Alan M. Polyglutamine Tract Expansion Increases S-Nitrosylation of Huntingtin and Ataxin-1
author_facet	Ni, Chun-Lun Seth, Divya Fonseca, Fabio Vasconcelos Wang, Liwen Xiao, Tsan Sam Gruber, Phillip Sy, Man-Sun Stamler, Jonathan S. Tartakoff, Alan M.
author_sort	Ni, Chun-Lun
title	Polyglutamine Tract Expansion Increases S-Nitrosylation of Huntingtin and Ataxin-1
title_short	Polyglutamine Tract Expansion Increases S-Nitrosylation of Huntingtin and Ataxin-1
title_full	Polyglutamine Tract Expansion Increases S-Nitrosylation of Huntingtin and Ataxin-1
title_fullStr	Polyglutamine Tract Expansion Increases S-Nitrosylation of Huntingtin and Ataxin-1
title_full_unstemmed	Polyglutamine Tract Expansion Increases S-Nitrosylation of Huntingtin and Ataxin-1
title_sort	polyglutamine tract expansion increases s-nitrosylation of huntingtin and ataxin-1
description	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.
publisher	Public Library of Science
publishDate	2016
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5033456/
_version_	1613658849003175936

Polyglutamine Tract Expansion Increases S-Nitrosylation of Huntingtin and Ataxin-1

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