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Title: The mechanisms of sirtuin 2-mediated exacerbation of alpha-synuclein toxicity in models of Parkinson disease

Author
item MACHADO DE OLIVEIRAR, RITA - Universidade Nova De Lisboa
item MIRNDA, HUGO - Universidade Nova De Lisboa
item FRANCELLE, FRANCESCA - University Of Gottingen
item PINHO, RAQUEL - University Of Gottingen
item SZEGO, EVA - University Of Gottingen
item MARTINHO, RENATO - University Of Lisbon
item MUNARI, FRANCESCA - Max Planck Institute For Biophysical Chemistry
item LAZARO, DIANA - University Of Gottingen
item MONIOT, SEBASTIEN - University Of Bayreuth
item GUERREIRO, PATRÍCIA - University Of Gottingen
item TONG, QIANG - Children'S Nutrition Research Center (CNRC)

Submitted to: PLoS Biology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/3/2017
Publication Date: 3/3/2017
Citation: Machado De Oliveirar, R., Mirnda, H.V., Francelle, F., Pinho, R., Szego, E.M., Martinho, R., Munari, F., Lazaro, D.F., Moniot, S., Guerreiro, P., Tong, Q. 2017. The mechanisms of sirtuin 2-mediated exacerbation of alpha-synuclein toxicity in models of Parkinson disease. PLoS Biology. 15(3):e2000374.

Interpretive Summary: This study investigates the role of the sirtuin 2 gene in age-associated neurodegenerative disorders such as Alzheimer and Parkinson disease. This study uncovered a link between sirtuin 2 and a-synuclein. It is known that accumulation of a-synuclein protein clumps in neurons causes Parkinson disease. We found that a-synuclein protein is chemically modified (acetylated) and this type of chemical modification can be removed (de-acetylated) by sirtuin 2. Genetic increase or decrease of sirtuin 2 levels in cells or in mice led to corresponding changes of the chemical modification (acetylation) of a-synuclein and its accumulation. Strikingly, changes that prevented the chemical modification (acetylation) of a-synuclein increased its toxicity in the brain areas that are affected by Parkinson's disease in rats. Our study identifies a novel pathway to regulate the development of Parkinson's disease. It is possible that inhibiting sirtuin 2 may prevent or alleviate the development of Parkinson's disease.

Technical Abstract: 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 a-synuclein, the major component of the pathognomonic protein inclusions in PD and other synucleinopathies. We found that a-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 a-synuclein acetylation, its aggregation, and autophagy. Strikingly, mutants blocking acetylation exacerbate a-synuclein toxicity in vivo, in the substantia nigra of rats. Our study identifies a-synuclein acetylation as a key regulatory mechanism governing a-synuclein aggregation and toxicity, demonstrating the potential therapeutic value of sirtuin 2 inhibition in synucleinopathies.