English
 
Help Privacy Policy Disclaimer
  Advanced SearchBrowse

Item

ITEM ACTIONSEXPORT

Released

Journal Article

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

MPS-Authors
/persons/resource/persons71698

Munari,  F.
Research Group of Protein Structure Determination using NMR, MPI for biophysical chemistry, Max Planck Society;

/persons/resource/persons79054

Fonseca,  L.
Research Group of Protein Structure Determination using NMR, MPI for biophysical chemistry, Max Planck Society;

/persons/resource/persons14824

Becker,  S.
Department of NMR Based Structural Biology, MPI for biophysical chemistry, Max Planck Society;

/persons/resource/persons16093

Zweckstetter,  M.
Research Group of Protein Structure Determination using NMR, MPI for biophysical chemistry, Max Planck Society;

External Resource
No external resources are shared
Fulltext (public)

2418345.pdf
(Publisher version), 3MB

Supplementary Material (public)

2418345_Suppl.htm
(Supplementary material), 273KB

Citation

de Oliveira, R. M., Miranda, H. V., Francelle, L., Pinho, R., Szegö, E. M., Martinho, R., et al. (2017). The mechanism of sirtuin 2–mediated exacerbation of alpha-synuclein toxicity in models of Parkinson disease. PLoS Biology, 15(3): e2000374. doi:10.1371/journal.pbio.2000374.


Cite as: http://hdl.handle.net/11858/00-001M-0000-002C-E85B-2
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