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The mechanism of sirtuin 2–mediated exacerbation of alpha-synuclein toxicity in models of Parkinson disease
Publication . de Oliveira, Rita M; Vicente Miranda, H.; Francelle, L.; Pinho, R.; Szegö, É.M.; Martinho, R.; Munari, F.; Lázaro, D.F.; Moniot, S.; Guerreiro, P.; Fonseca, L.; Marijanovic, Z.; Antas, P.; Gerhardt, E.; Enguita, F.J.; Fauvet, B.; Penque, D.; Pais, T.F.; Tong, Q.; Becker, S.; Kügler, S.; Lashuel, H.A.; Steegborn, C.; Zweckstetter, M.; Outeiro, T.F.; NOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM); Centro de Estudos de Doenças Crónicas (CEDOC); PLOS - Public Library of Science
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. © 2017 de Oliveira et al.
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Fundação para a Ciência e a Tecnologia
Programa de financiamento
3599-PPCDT
Número da atribuição
105215