Autor(es):
de Oliveira, Rita Machado ; 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
Data: 2017
Identificador Persistente: http://hdl.handle.net/10400.18/5465
Origem: Repositório Científico do Instituto Nacional de Saúde
Assunto(s): 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
Descrição
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.
