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The mechanism of sirtuin 2-mediated exacerbation of alpha-synuclein toxicity in models of Parkinson disease

2017-03-03Journal article Open access
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dc.contributor.authorde Oliveira, Rita Machado
dc.contributor.authorVicente Miranda, Hugo
dc.contributor.authorFrancelle, Laetitia
dc.contributor.authorPinho, Raquel
dc.contributor.authorSzegö, Éva M.
dc.contributor.authorMartinho, Renato
dc.contributor.authorMunari, Francesca
dc.contributor.authorLázaro, Diana F.
dc.contributor.authorMoniot, Sébastien
dc.contributor.authorGuerreiro, Patrícia
dc.contributor.authorFonseca-Ornelas, Luis
dc.contributor.authorMarijanovic, Zrinka
dc.contributor.authorAntas, Pedro
dc.contributor.authorGerhardt, Ellen
dc.contributor.authorEnguita, Francisco Javier
dc.contributor.authorFauvet, Bruno
dc.contributor.authorPenque, Deborah
dc.contributor.authorPais, Teresa Faria
dc.contributor.authorTong, Qiang
dc.contributor.authorBecker, Stefan
dc.contributor.authorKügler, Sebastian
dc.contributor.authorLashuel, Hilal Ahmed
dc.contributor.authorSteegborn, Clemens
dc.contributor.authorZweckstetter, Markus
dc.contributor.authorOuteiro, Tiago Fleming
dc.date.accessioned2018-03-22T19:43:44Z
dc.date.available2018-03-22T19:43:44Z
dc.date.issued2017-03-03
dc.description.abstractSirtuin genes have been associated with aging and are known to affect multiple cellular pathways. Sirtuin 2 was previously shown to modulate proteotoxicity associated with age-associated neurodegenerative disorders such as Alzheimer and Parkinson disease (PD). However, the precise molecular mechanisms involved remain unclear. Here, we provide mechanistic insight into the interplay between sirtuin 2 and α-synuclein, the major component of the pathognomonic protein inclusions in PD and other synucleinopathies. We found that α-synuclein is acetylated on lysines 6 and 10 and that these residues are deacetylated by sirtuin 2. Genetic manipulation of sirtuin 2 levels in vitro and in vivo modulates the levels of α-synuclein acetylation, its aggregation, and autophagy. Strikingly, mutants blocking acetylation exacerbate α-synuclein toxicity in vivo, in the substantia nigra of rats. Our study identifies α-synuclein acetylation as a key regulatory mechanism governing α-synuclein aggregation and toxicity, demonstrating the potential therapeutic value of sirtuin 2 inhibition in synucleinopathies.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationPLoS Biol. 2017 Mar 3;15(3):e2000374. doi: 10.1371/journal.pbio.2000374. eCollection 2017 Mar.pt_PT
dc.identifier.doi10.1371/journal.pbio.2000374pt_PT
dc.identifier.issn1544-9173
dc.identifier.urihttp://hdl.handle.net/10400.18/5465
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherPublic Library of Sciencept_PT
dc.relation.publisherversionhttp://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.2000374pt_PT
dc.subject1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridinept_PT
dc.subjectAcetylationpt_PT
dc.subjectAnimalspt_PT
dc.subjectAutophagypt_PT
dc.subjectCell Membranept_PT
dc.subjectCells, Culturedpt_PT
dc.subjectCerebral Cortexpt_PT
dc.subjectDisease Models, Animalpt_PT
dc.subjectDopaminergic Neuronspt_PT
dc.subjectGene Deletionpt_PT
dc.subjectGene Knockdown Techniquespt_PT
dc.subjectHEK293 Cellspt_PT
dc.subjectHumanspt_PT
dc.subjectLysinept_PT
dc.subjectMice, Inbred C57BLpt_PT
dc.subjectMice, Knockoutpt_PT
dc.subjectMutationpt_PT
dc.subjectNeuroprotectionpt_PT
dc.subjectParkinson Diseasept_PT
dc.subjectProtein Aggregatespt_PT
dc.subjectProtein Bindingpt_PT
dc.subjectSirtuin 2pt_PT
dc.subjectalpha-Synucleinpt_PT
dc.subjectGenómica Funcional e Estruturalpt_PT
dc.titleThe mechanism of sirtuin 2-mediated exacerbation of alpha-synuclein toxicity in models of Parkinson diseasept_PT
dc.typejournal article
dspace.entity.typePublication
oaire.citation.issue3pt_PT
oaire.citation.startPagee2000374pt_PT
oaire.citation.titlePLoS Biologypt_PT
oaire.citation.volume15pt_PT
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT

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