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

Title data

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. Vol. 15 (3 March 2017) Issue 3 . - e2000374.
ISSN 1545-7885
DOI: https://doi.org/10.1371/journal.pbio.2000374

Abstract in another language

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.

Further data

Item Type: Article in a journal
Refereed: Yes
Institutions of the University: Faculties > Faculty of Biology, Chemistry and Earth Sciences > Department of Chemistry > Chair Biochemistry > Chair Biochemistry - Univ.-Prof. Dr. Clemens Steegborn
Faculties
Faculties > Faculty of Biology, Chemistry and Earth Sciences
Faculties > Faculty of Biology, Chemistry and Earth Sciences > Department of Chemistry
Faculties > Faculty of Biology, Chemistry and Earth Sciences > Department of Chemistry > Chair Biochemistry
Result of work at the UBT: No
DDC Subjects: 500 Science > 540 Chemistry
500 Science > 570 Life sciences, biology
Date Deposited: 06 Apr 2017 08:47
Last Modified: 19 Apr 2018 10:41
URI: https://eref.uni-bayreuth.de/id/eprint/36765