Please use this identifier to cite or link to this item: http://hdl.handle.net/10316/20850
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dc.contributor.authorRibeiro, Márcio-
dc.contributor.authorRosenstock, Tatiana-
dc.contributor.authorCunha-Oliveira, Teresa-
dc.contributor.authorFerreira, Ildete-
dc.contributor.authorOliveira, Catarina R.-
dc.contributor.authorRego, Ana Cristina-
dc.date.accessioned2012-10-16T08:54:47Z-
dc.date.available2012-10-16T08:54:47Z-
dc.date.issued2012-11-15-
dc.identifier.urihttp://hdl.handle.net/10316/20850-
dc.description.abstractHuntington’s disease (HD) is a CAG repeat disorder affecting the HD gene, which encodes for huntingtin (Htt) and is characterized by prominent cell death in the striatum. Oxidative stress was previously implicated in HD neurodegeneration, but the role of the major endogenous antioxidant system, the glutathione redox cycle, has been less studied following expression of full-length mutant Htt (FL-mHtt). Thus, in this work we analyzed the glutathione system in striatal cells derived from HD knock-in mice expressing mutant Htt versus wild-type cells. Mutant cells showed increased intracellular reactive oxygen species (ROS) and caspase-3 activity, which were significantly prevented following treatment with glutathione ethyl ester. Interestingly, mutant cells exhibited an increase in intracellular levels of both reduced and oxidized forms of glutathione, and enhanced activities of glutathione peroxidase (GPx) and glutathione reductase (GRed). Furthermore, glutathione-S-transferase (GST) and γ-glutamyl transpeptidase (γ–GT) activities were also increased in mutant cells. Nevertheless, glutamate-cysteine ligase (GCL) and glutathione synthetase (GS) activities and levels of GCL catalytic subunit were decreased in cells expressing FL-mHtt, highly suggesting decreased de novo synthesis of glutathione. Enhanced intracellular total glutathione, despite decreased synthesis, could be explained by decreased extracellular glutathione in mutant cells. This occurred concomitantly with decreased mRNA expression levels and activity of the multidrug resistance protein 1 (Mrp1), a transport protein that mediates cellular export of glutathione disulfide and glutathione conjugates. Additionally, inhibition of Mrp1 enhanced intracellular GSH in wild-type cells only. These data suggest that FL-mHtt affects the export of glutathione by decreasing the expression of Mrp1. Data further suggest that boosting of GSH-related antioxidant defense mechanisms induced by FL-mHtt is insufficient to counterbalance increased ROS formation and emergent apoptotic features in HD striatal cells.por
dc.language.isoengpor
dc.publisherFree Radical Biology and Medicinepor
dc.rightsopenAccesspor
dc.titleGlutathione redox cycle dysregulation in Huntington’s disease knock-in striatal cellspor
dc.typearticlepor
degois.publication.firstPage1857por
degois.publication.lastPage1867por
degois.publication.titleFree Radical Biology and Medicinepor
dc.relation.publisherversionhttp://www.sciencedirect.com/science/article/pii/S0891584912011276por
dc.peerreviewedYespor
dc.identifier.doi10.1016/j.freeradbiomed.2012.09.004-
degois.publication.volume53por
item.grantfulltextopen-
item.languageiso639-1en-
item.fulltextCom Texto completo-
crisitem.author.deptCNC - Center for Neuroscience and Cell Biology-
crisitem.author.deptFaculty of Medicine-
crisitem.author.deptFaculty of Medicine-
crisitem.author.parentdeptUniversity of Coimbra-
crisitem.author.parentdeptUniversity of Coimbra-
crisitem.author.researchunitCNC - Center for Neuroscience and Cell Biology-
crisitem.author.researchunitCNC - Center for Neuroscience and Cell Biology-
crisitem.author.orcid0000-0002-7382-0339-
crisitem.author.orcid0000-0001-6942-4328-
crisitem.author.orcid0000-0003-0700-3776-
Appears in Collections:I&D CNC - Artigos em Revistas Internacionais
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