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

Lookup NU author(s): Professor Tiago OuteiroORCiD



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© 2017 de Oliveira et al. 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.

Publication metadata

Author(s): de Oliveira RM, Vicente Miranda H, Francelle L, Pinho R, Szego EM, Martinho R, Munari F, Lazaro DF, Moniot S, Guerreiro P, Fonseca L, Marijanovic Z, Antas P, Gerhardt E, Enguita FJ, Fauvet B, Penque D, Pais TF, Tong Q, Becker S, Kugler S, Lashuel HA, Steegborn C, Zweckstetter M, Outeiro TF

Publication type: Article

Publication status: Published

Journal: PLoS Biology

Year: 2017

Volume: 15

Issue: 3

Online publication date: 03/03/2017

Acceptance date: 03/02/2017

Date deposited: 20/12/2017

ISSN (print): 1544-9173

ISSN (electronic): 1545-7885

Publisher: Public Library of Science


DOI: 10.1371/journal.pbio.2000374

PubMed id: 28257421


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AFI #14834
AHA-TX 17220055