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

SUBMITTER: de Oliveira RM 

PROVIDER: S-EPMC5336201 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature