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

• Autor(a) principal: de Oliveira, Rita Machado
• Data de Publicação: 2017
• Outros Autores: Vicente Miranda, Hugo, Francelle, Laetitia, Pinho, Raquel, Szegö, Éva M., Martinho, Renato, Munari, Francesca, Lázaro, Diana F., Moniot, Sébastien, Guerreiro, Patrícia, Fonseca-Ornelas, Luis, Marijanovic, Zrinka, Antas, Pedro, Gerhardt, Ellen, Enguita, Francisco Javier, Fauvet, Bruno, Penque, Deborah, Pais, Teresa Faria, Tong, Qiang, Becker, Stefan, Kügler, Sebastian, Lashuel, Hilal Ahmed, Steegborn, Clemens, Zweckstetter, Markus, Outeiro, Tiago Fleming
• Tipo de documento: Artigo
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10400.18/5465
• topic: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Acetylation; Animals; Autophagy; Cell Membrane; Cells, Cultured; Cerebral Cortex; Disease Models, Animal; Dopaminergic Neurons; Gene Deletion; Gene Knockdown Techniques; HEK293 Cells; Humans; Lysine; Mice, Inbred C57BL; Mice, Knockout; Mutation; Neuroprotection; Parkinson Disease; Protein Aggregates; Protein Binding; Sirtuin 2; alpha-Synuclein; Genómica Funcional e Estrutural

Sirtuin 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.