de Oliveira, Rita MachadoVicente Miranda, HugoFrancelle, LaetitiaPinho, RaquelSzegö, Éva M.Martinho, RenatoMunari, FrancescaLázaro, Diana F.Moniot, SébastienGuerreiro, PatríciaFonseca-Ornelas, LuisMarijanovic, ZrinkaAntas, PedroGerhardt, EllenEnguita, Francisco JavierFauvet, BrunoPenque, DeborahPais, Teresa FariaTong, QiangBecker, StefanKügler, SebastianLashuel, Hilal AhmedSteegborn, ClemensZweckstetter, MarkusOuteiro, Tiago Fleming2018-03-222018-03-222017-03-03PLoS Biol. 2017 Mar 3;15(3):e2000374. doi: 10.1371/journal.pbio.2000374. eCollection 2017 Mar.1544-9173http://hdl.handle.net/10400.18/5465Sirtuin 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.eng1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridineAcetylationAnimalsAutophagyCell MembraneCells, CulturedCerebral CortexDisease Models, AnimalDopaminergic NeuronsGene DeletionGene Knockdown TechniquesHEK293 CellsHumansLysineMice, Inbred C57BLMice, KnockoutMutationNeuroprotectionParkinson DiseaseProtein AggregatesProtein BindingSirtuin 2alpha-SynucleinGenómica Funcional e Estruturaljournal article10.1371/journal.pbio.2000374