Silva Guerreiro, Patricia da

[["dc.bibliographiccitation.firstpage","2603"],["dc.bibliographiccitation.issue","19"],["dc.bibliographiccitation.journal","The EMBO Journal"],["dc.bibliographiccitation.lastpage","2616"],["dc.bibliographiccitation.volume","32"],["dc.contributor.author","Pais, Teresa Faria"],["dc.contributor.author","Szego, Eva M."],["dc.contributor.author","Marques, Oldriska"],["dc.contributor.author","Miller-Fleming, Leonor"],["dc.contributor.author","Antas, Pedro"],["dc.contributor.author","Guerreiro, Patricia S."],["dc.contributor.author","de Oliveira, Rita Machado"],["dc.contributor.author","Kasapoglu, Burcu"],["dc.contributor.author","Outeiro, Tiago Fleming"],["dc.date.accessioned","2018-11-07T09:18:44Z"],["dc.date.available","2018-11-07T09:18:44Z"],["dc.date.issued","2013"],["dc.description.abstract","Deleterious sustained inflammation mediated by activated microglia is common to most of neurologic disorders. Here, we identified sirtuin 2 (SIRT2), an abundant deacetylase in the brain, as a major inhibitor of microglia-mediated inflammation and neurotoxicity. SIRT2-deficient mice (SIRT2(-/-)) showed morphological changes in microglia and an increase in pro-inflammatory cytokines upon intracortical injection of lipopolysaccharide (LPS). This response was associated with increased nitrotyrosination and neuronal cell death. Interestingly, manipulation of SIRT2 levels in microglia determined the response to Toll-like receptor (TLR) activation. SIRT2 overexpression inhibited microglia activation in a process dependent on serine 331 (S331) phosphorylation. Conversely, reduction of SIRT2 in microglia dramatically increased the expression of inflammatory markers, the production of free radicals, and neurotoxicity. Consistent with increased NF-kappa B-dependent transcription of inflammatory genes, NF-kappa B was found hyperacetylated in the absence of SIRT2, and became hypoacetylated in the presence of S331A mutant SIRT2. This finding indicates that SIRT2 functions as a 'gatekeeper', preventing excessive microglial activation through NF-kappa B deacetylation. Our data uncover a novel role for SIRT2 opening new perspectives for therapeutic intervention in neuroinflammatory disorders."],["dc.identifier.doi","10.1038/emboj.2013.200"],["dc.identifier.isi","000325276800008"],["dc.identifier.pmid","24013120"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/28474"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Nature Publishing Group"],["dc.relation.issn","0261-4189"],["dc.title","The NAD-dependent deacetylase sirtuin 2 is a suppressor of microglial activation and brain inflammation"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","113"],["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","NeuroMolecular Medicine"],["dc.bibliographiccitation.lastpage","121"],["dc.bibliographiccitation.volume","19"],["dc.contributor.author","Guerreiro, Patricia S."],["dc.contributor.author","Coelho, Joana E."],["dc.contributor.author","Sousa-Lima, Ines"],["dc.contributor.author","Macedo, Paula"],["dc.contributor.author","Lopes, Luisa Vaqueiro"],["dc.contributor.author","Outeiro, Tiago Fleming"],["dc.contributor.author","Pais, Teresa Faria"],["dc.date.accessioned","2018-11-07T10:26:46Z"],["dc.date.available","2018-11-07T10:26:46Z"],["dc.date.issued","2017"],["dc.description.abstract","The protein alpha-synuclein (alpha-Syn) interferes with glucose and lipid uptake and also activates innate immune cells. However, it remains unclear whether alpha-Syn or its familial mutant forms contribute to metabolic alterations and inflammation in synucleinopathies, such as Parkinson's disease (PD). Here, we address this issue in transgenic mice for the mutant A53T human alpha-Syn (alpha-SynA53T), a mouse model of synucleinopathies. At 9.5 months of age, mice overexpressing alpha-SynA53T (homozygous) had a significant reduction in weight, exhibited improved locomotion and did not show major motor deficits compared with control transgenic mice (heterozygous). At 17 months of age, alpha-SynA53T overexpression promoted general reduction in grip strength and deficient hindlimb reflex and resulted in severe disease and mortality in 50 % of the mice. Analysis of serum metabolites further revealed decreased levels of cholesterol, triglycerides and non-esterified fatty acids (NEFA) in alpha-SynA53T-overexpressing mice. In fed conditions, these mice also showed a significant decrease in serum insulin without alterations in blood glucose. In addition, assessment of inflammatory gene expression in the brain showed a significant increase in TNF-alpha mRNA but not of IL-1 beta induced by alpha-SynA53T overexpression. Interestingly, the brain mRNA levels of Sirtuin 2 (Sirt2), a deacetylase involved in both metabolic and inflammatory pathways, were significantly reduced. Our findings highlight the relevance of the mechanisms underlying initial weight loss and hyperactivity as early markers of synucleinopathies. Moreover, we found that changes in blood metabolites and decreased brain Sirt2 gene expression are associated with motor deficits."],["dc.identifier.doi","10.1007/s12017-016-8435-5"],["dc.identifier.isi","000396029500011"],["dc.identifier.pmid","27535567"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/43115"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","PUB_WoS_Import"],["dc.publisher","Humana Press Inc"],["dc.relation.issn","1559-1174"],["dc.relation.issn","1535-1084"],["dc.title","Mutant A53T alpha-Synuclein Improves Rotarod Performance Before Motor Deficits and Affects Metabolic Pathways"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]