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

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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 F. ; Tong, Qiang ; Becker, Stefan ; Kügler, Sebastian ; Lashuel, Hilal Ahmed ; Steegborn, Clemens ; Zweckstetter, Markus ; Outeiro, Tiago Fleming:
The mechanism of sirtuin 2-mediated exacerbation of alpha-synuclein toxicity in models of Parkinson disease.
In: PLoS biology. Bd. 15 (März 2017) Heft 3 . - e2000374.
ISSN 1545-7885
DOI: 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 - 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: 27 Jul 2017 06:53
URI: https://eref.uni-bayreuth.de/id/eprint/36765