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

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.

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 Urheber:
de Oliveira, R. M., Autor
Miranda, H. V., Autor
Francelle, L., Autor
Pinho, R., Autor
Szegö, E. M., Autor
Martinho, R., Autor
Munari, F.1, Autor           
Lázaro, D. F., Autor
Moniot, S., Autor
Guerreiro, P., Autor
Fonseca, L.1, Autor           
Marijanovic, Z., Autor
Antas, P., Autor
Gerhardt, E., Autor
Enguita, F. J., Autor
Fauvet, B., Autor
Penque, D., Autor
Pais, T. F., Autor
Tong, Q., Autor
Becker, S.2, Autor           
Kügler, S., AutorLashuel, H. A., AutorSteegborn, C., AutorZweckstetter, M.1, Autor           Outeiro, T. F., Autor mehr..
Affiliations:
1Research Group of Protein Structure Determination using NMR, MPI for biophysical chemistry, Max Planck Society, ou_578571              
2Department of NMR Based Structural Biology, MPI for biophysical chemistry, Max Planck Society, ou_578567              

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 Zusammenfassung: 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

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Sprache(n): eng - English
 Datum: 2017-03-03
 Publikationsstatus: Online veröffentlicht
 Seiten: -
 Ort, Verlag, Ausgabe: -
 Inhaltsverzeichnis: -
 Art der Begutachtung: Expertenbegutachtung
 Identifikatoren: DOI: 10.1371/journal.pbio.2000374
 Art des Abschluß: -

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Titel: PLoS Biology
Genre der Quelle: Zeitschrift
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Seiten: 27 Band / Heft: 15 (3) Artikelnummer: e2000374 Start- / Endseite: - Identifikator: -