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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.
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
URL: https://doi.org/10.1371/journal.pbio.2000374
DOI: 10.1371/journal.pbio.2000374
PubMed id: 28257421
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