Antas P

Becker S

de Oliveira RM

Enguita FJ

Fauvet B

Fonseca L

Francelle L

Gerhardt E

Guerreiro P

Kugler S

Lashuel HA

Lazaro DF

Marijanovic Z

Martinho R

Moniot S

Munari F

Outeiro TF

Pais TF

Penque D

Pinho R

Steegborn C

Szego EM

Tong Q

Vicente Miranda H

Zweckstetter M

\ua9 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

Newcastle University E-Prints

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

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

Abstract

Similar works

Full text

Available Versions

Newcastle University E-Prints