Sirtuin (SIRT) proteins are deacylases with important roles in ageing. For example, SIRT2 has been shown to modulate, through a poorly understood mechanism, the aggregation and toxicity of α-synuclein (α-syn), which is associated with neurodegenerative disorders such as Parkinson disease. Outeiro and colleagues now reveal that SIRT2 deacetylates α-syn at two amino-terminal Lys residues, thereby favouring α-syn aggregation.
The authors first showed that SIRT2 directly interacts with α-syn when the two proteins were co-expressed in cultured human cells, and, in a more physiologically relevant context, by co-immunoprecipating α-syn with SIRT2 from mouse brain extracts. Moreover, α-syn was deacetylated by SIRT2 at Lys6 and Lys10. Consistent with this finding, acetylation of α-syn does not decrease when immunoprecipitation assays are performed with an inactive SIRT2 mutant, and α-syn is hyperacetylated in the brains of Sirt2 knockout mice.
To assess whether SIRT2-dependent deacetylation influences the aggregation of α-syn, SIRT2 levels were reduced by RNAi in a cellular model of Parkinson disease in which α-syn has a high propensity for aggregation. Remarkably, this resulted in fewer α-syn inclusions, increased solubility and reduced size of α-syn-containing protein aggregates. Furthermore, mutating Lys6 and Lys10 to create α-syn mutants that either mimic constitutive acetylation or are acetylation-resistant, showed that acetylation at these residues prevents aggregation.
SIRT2-mediated deacetylation of α-syn promotes toxic protein aggregation
The authors further investigated the cellular and physiological impact of SIRT2-mediated deacetylation of α-syn. They found that SIRT2 knockdown decreased the cytotoxicity of the protein inclusions, as indicated by a reduction in the amount of lactate dehydrogenase released from cells. Also, interestingly, although the basal level of autophagy was unaffected by SIRT2knockdown, in the presence of α-syn aggregates, SIRT2 knockdown potentiated autophagy to efficiently clear the aggregates. Last, expression of acetylation-resistant or acetylation-mimic α-syn mutants in cultured neurons and in vivo (in the rat substantia nigra) showed that lower levels of α-syn acetylation induce neuronal loss.
Together, these results indicate that SIRT2-mediated deacetylation of α-syn promotes toxic protein aggregation, and suggest that the inhibition of SIRT2 activity could be a potential therapeutic avenue for the treatment of neurodegenerative diseases.
References
de Oliveira, R. M. et al. The mechanisms of sirtuin 2-mediated exacerbation of alpha-synuclein toxicity in models of Parkinson disease. PLOS Biol. https://doi.org/10.1371/journal.pbio.2000374 15, e2000374 (2017)
Related links
Related links
Related links in Nature Research
Rights and permissions
About this article
Cite this article
Baumann, K. Counteracting toxic protein aggregation. Nat Rev Mol Cell Biol 18, 214 (2017). https://doi.org/10.1038/nrm.2017.24
Published:
Issue Date:
DOI: https://doi.org/10.1038/nrm.2017.24