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

R.M. de Oliveira, H. Vicente Miranda, L. Francelle, R. Pinho, É.M. Szegö, R. Martinho, F. Munari, D.F. Lázaro, S. Moniot, P. Guerreiro, L. Fonseca, Z. Marijanovic, P. Antas, E. Gerhardt, F.J. Enguita, B. Fauvet, D. Penque, T.F. Pais, Q. Tong, S. BeckerS. Kügler, H.A. Lashuel, C. Steegborn, M. Zweckstetter, T.F. Outeiro

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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. © 2017 de Oliveira et al.
Original languageEnglish
Pages (from-to)Online
Number of pages27
JournalPLoS Biology
Volume15
Issue number3
DOIs
Publication statusPublished - Mar 2017

Keywords

  • 1,2,3,6 tetrahydro 1 methyl 4 phenylpyridine
  • alpha synuclein
  • lysine
  • protein aggregate
  • protein binding
  • sirtuin 2
  • acetylation
  • animal
  • autophagy
  • brain cortex
  • C57BL mouse
  • cell culture
  • cell membrane
  • disease model
  • dopaminergic nerve cell
  • drug effects
  • gene deletion
  • gene silencing
  • genetics
  • HEK293 cell line
  • human
  • knockout mouse
  • metabolism
  • mutation
  • neuroprotection
  • Parkinson disease
  • pathology
  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
  • Acetylation
  • alpha-Synuclein
  • 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

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  • Cite this

    de Oliveira, R. M., Vicente Miranda, H., Francelle, L., Pinho, R., Szegö, É. M., Martinho, R., Munari, F., Lázaro, D. F., Moniot, S., Guerreiro, P., Fonseca, L., Marijanovic, Z., Antas, P., Gerhardt, E., Enguita, F. J., Fauvet, B., Penque, D., Pais, T. F., Tong, Q., ... Outeiro, T. F. (2017). The mechanism of sirtuin 2–mediated exacerbation of alpha-synuclein toxicity in models of Parkinson disease. PLoS Biology, 15(3), Online. https://doi.org/10.1371/journal.pbio.2000374