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

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.

Keywords

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine Acetylation Animals Autophagy Cell Membrane Cells, Cultured Cerebral Cortex Disease Models, Animal Dopaminergic Neurons Gene Deletion Gene Knockdown Techniques HEK293 Cells Humans Lysine Mice, Inbred C57BL Mice, Knockout Mutation Neuroprotection Parkinson Disease Protein Aggregates Protein Binding Sirtuin 2 alpha-Synuclein Genómica Funcional e Estrutural