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de Oliveira, Rita Machado ; Vicente Miranda, Hugo ; Francelle, Laetitia ; Pinho, Raquel ; Szegö, Éva M. ; Martinho, Renato ; Munari, Francesca ; Lázaro, Diana F. ; Moniot, Sébastien ; Guerreiro, Patrícia ; Fonseca, Luis ; Marijanovic, Zrinka ; Antas, Pedro ; Gerhardt, Ellen ; Enguita, Francisco Javier ; Fauvet, Bruno ; Penque, Deborah ; Pais, Teresa Faria ; Tong, Qiang ; Becker, Stefan ; Kügler, Sebastian ; Lashuel, Hilal Ahmed ; Steegborn, Clemens ; Zweckstetter, Markus ; Outeiro, Tiago F.:
The mechanism of sirtuin 2-mediated exacerbation of alpha-synuclein toxicity in models of Parkinson disease.
In: PLoS Biology.
Bd. 15
(2017)
Heft 3
.
- No. e2000374.
ISSN 1545-7885
DOI: https://doi.org/10.1371/journal.pbio.2000374
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.
Weitere Angaben
| Publikationsform: | Artikel in einer Zeitschrift |
|---|---|
| Begutachteter Beitrag: | Ja |
| Institutionen der Universität: | Fakultäten > Fakultät für Biologie, Chemie und Geowissenschaften > Fachgruppe Chemie > Lehrstuhl Biochemie > Lehrstuhl Biochemie I - Proteinbiochemie der Signaltransduktion - Univ.-Prof. Dr. Clemens Steegborn Fakultäten Fakultäten > Fakultät für Biologie, Chemie und Geowissenschaften Fakultäten > Fakultät für Biologie, Chemie und Geowissenschaften > Fachgruppe Chemie Fakultäten > Fakultät für Biologie, Chemie und Geowissenschaften > Fachgruppe Chemie > Lehrstuhl Biochemie |
| Titel an der UBT entstanden: | Nein |
| Themengebiete aus DDC: | 500 Naturwissenschaften und Mathematik > 540 Chemie 500 Naturwissenschaften und Mathematik > 570 Biowissenschaften; Biologie |
| Eingestellt am: | 06 Apr 2017 08:47 |
| Letzte Änderung: | 31 Aug 2022 13:56 |
| URI: | https://eref.uni-bayreuth.de/id/eprint/36765 |