Utilize este identificador para referenciar este registo: http://hdl.handle.net/10400.18/5465
Título: The mechanism of sirtuin 2-mediated exacerbation of alpha-synuclein toxicity in models of Parkinson disease
Autor: 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
Palavras-chave: 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
Data: 3-Mar-2017
Editora: Public Library of Science
Citação: PLoS Biol. 2017 Mar 3;15(3):e2000374. doi: 10.1371/journal.pbio.2000374. eCollection 2017 Mar.
Resumo: 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.
Peer review: yes
URI: http://hdl.handle.net/10400.18/5465
DOI: 10.1371/journal.pbio.2000374
ISSN: 1544-9173
Versão do Editor: http://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.2000374
Aparece nas colecções:DGH - Artigos em revistas internacionais

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