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

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 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.

• Authors: Rita Machado de Oliveira, Hugo Vicente Miranda, Laetitia Francelle, Raquel Pinho, Éva M Szegö, Renato Martinho, Francesca Munari, Diana F Lázaro, Sébastien Moniot, Patrícia Guerreiro, Luis Fonseca-Ornelas, Zrinka Marijanovic, Pedro Antas, Ellen Gerhardt, Francisco Javier Enguita, Bruno Fauvet, Deborah Penque, Teresa Faria Pais, Qiang Tong, Stefan Becker, Sebastian Kügler, Hilal Ahmed Lashuel, Clemens Steegborn, Markus Zweckstetter, Tiago Fleming Outeiro
• Journal: PLoS biology (PLoS Biol) Vol. 15 Issue 3 Pg. e2000374 (03 2017) ISSN: 1545-7885 [Electronic] United States
• PMID: 28257421 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, Non-U.S. Gov't)

Chemical References

• Protein Aggregates
• alpha-Synuclein
• 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
• Sirtuin 2
• Lysine

Topics

• 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
• Acetylation (drug effects)
• Animals
• Autophagy (drug effects)
• Cell Membrane (drug effects, metabolism)
• Cells, Cultured
• Cerebral Cortex (pathology)
• Disease Models, Animal
• Dopaminergic Neurons (drug effects, metabolism)
• Gene Deletion
• Gene Knockdown Techniques
• HEK293 Cells
• Humans
• Lysine (metabolism)
• Mice, Inbred C57BL
• Mice, Knockout
• Mutation (genetics)
• Neuroprotection (drug effects)
• Parkinson Disease (metabolism, pathology)
• Protein Aggregates (drug effects)
• Protein Binding
• Sirtuin 2 (metabolism)
• alpha-Synuclein (toxicity)