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The mechanism of sirtuin 2-mediated exacerbation of alpha-synuclein toxicity in models of Parkinson disease.
PLoS Biol. 2017 03; 15(3):e2000374.PB

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.

Links

Publisher Full Text
ncbi.nlm.nih.gov
dx.plos.org
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Authors+Show Affiliations

de Oliveira RM
CEDOC, NOVA Medical School, Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Lisboa, Portugal.
Vicente Miranda H
CEDOC, NOVA Medical School, Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Lisboa, Portugal.
Francelle L
Department of Neurodegeneration and Restorative Research, University Medical Center Göttingen, Göttingen, Germany.
Pinho R
Department of Neurodegeneration and Restorative Research, University Medical Center Göttingen, Göttingen, Germany. Faculty of Medicine, University of Porto, Porto, Portugal.
Szegö ÉM
Department of Neurodegeneration and Restorative Research, University Medical Center Göttingen, Göttingen, Germany.
Martinho R
Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.
Munari F
Department for NMR-based Structural Biology, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany. German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany.
Lázaro DF
Department of Neurodegeneration and Restorative Research, University Medical Center Göttingen, Göttingen, Germany.
Moniot S
Department of Biochemistry, University of Bayreuth, Bayreuth, Germany.
Guerreiro P
Department of Neurodegeneration and Restorative Research, University Medical Center Göttingen, Göttingen, Germany.
Fonseca-Ornelas L
Department for NMR-based Structural Biology, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany.
Marijanovic Z
Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.
Antas P
Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.
Gerhardt E
Department of Neurodegeneration and Restorative Research, University Medical Center Göttingen, Göttingen, Germany.
Enguita FJ
Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.
Fauvet B
Laboratory of Molecular and Chemical Biology of Neurodegeneration, Swiss Federal Institute of Technology Lausanne (EPFL), Lausanne, Switzerland.
Penque D
Laboratório de Proteómica, Departamento de Genética Humana, Instituto Nacional de Saúde Dr. Ricardo Jorge, Lisboa, Portugal.
Pais TF
Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.
Tong Q
USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, United States of America.
Becker S
Department for NMR-based Structural Biology, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany.
Kügler S
Department of Neurology, University Medical Center Göttingen, University of Göttingen, Göttingen, Germany.
Lashuel HA
Laboratory of Molecular and Chemical Biology of Neurodegeneration, Swiss Federal Institute of Technology Lausanne (EPFL), Lausanne, Switzerland.
Steegborn C
Department of Biochemistry, University of Bayreuth, Bayreuth, Germany.
Zweckstetter M
Department for NMR-based Structural Biology, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany. German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany. Department of Neurology, University Medical Center Göttingen, University of Göttingen, Göttingen, Germany.
Outeiro TF
CEDOC, NOVA Medical School, Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Lisboa, Portugal. Department of Neurodegeneration and Restorative Research, University Medical Center Göttingen, Göttingen, Germany. Max Planck Institute for Experimental Medicine, Göttingen, Germany. Center for Biostructural Imaging of Neurodegeneration, University Medical Center Göttingen, University of Göttingen, Göttingen, Germany.

MeSH

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridineAcetylationAnimalsAutophagyCell MembraneCells, CulturedCerebral CortexDisease Models, AnimalDopaminergic NeuronsGene DeletionGene Knockdown TechniquesHEK293 CellsHumansLysineMice, Inbred C57BLMice, KnockoutMutationNeuroprotectionParkinson DiseaseProtein AggregatesProtein BindingSirtuin 2alpha-Synuclein

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

28257421

Citation

de Oliveira, Rita Machado, et al. "The Mechanism of Sirtuin 2-mediated Exacerbation of Alpha-synuclein Toxicity in Models of Parkinson Disease." PLoS Biology, vol. 15, no. 3, 2017, pp. e2000374.
de Oliveira RM, Vicente Miranda H, Francelle L, et al. The mechanism of sirtuin 2-mediated exacerbation of alpha-synuclein toxicity in models of Parkinson disease. PLoS Biol. 2017;15(3):e2000374.
de Oliveira, R. M., Vicente Miranda, H., Francelle, L., Pinho, R., Szegö, É. M., Martinho, R., Munari, F., Lázaro, D. F., Moniot, S., Guerreiro, P., Fonseca-Ornelas, L., Marijanovic, Z., Antas, P., Gerhardt, E., Enguita, F. J., Fauvet, B., Penque, D., Pais, T. F., Tong, Q., ... Outeiro, T. F. (2017). The mechanism of sirtuin 2-mediated exacerbation of alpha-synuclein toxicity in models of Parkinson disease. PLoS Biology, 15(3), e2000374. https://doi.org/10.1371/journal.pbio.2000374
de Oliveira RM, et al. The Mechanism of Sirtuin 2-mediated Exacerbation of Alpha-synuclein Toxicity in Models of Parkinson Disease. PLoS Biol. 2017;15(3):e2000374. PubMed PMID: 28257421.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The mechanism of sirtuin 2-mediated exacerbation of alpha-synuclein toxicity in models of Parkinson disease. AU - de Oliveira,Rita Machado, AU - Vicente Miranda,Hugo, AU - Francelle,Laetitia, AU - Pinho,Raquel, AU - Szegö,Éva M, AU - Martinho,Renato, AU - Munari,Francesca, AU - Lázaro,Diana F, AU - Moniot,Sébastien, AU - Guerreiro,Patrícia, AU - Fonseca-Ornelas,Luis, AU - Marijanovic,Zrinka, AU - Antas,Pedro, AU - Gerhardt,Ellen, AU - Enguita,Francisco Javier, AU - Fauvet,Bruno, AU - Penque,Deborah, AU - Pais,Teresa Faria, AU - Tong,Qiang, AU - Becker,Stefan, AU - Kügler,Sebastian, AU - Lashuel,Hilal Ahmed, AU - Steegborn,Clemens, AU - Zweckstetter,Markus, AU - Outeiro,Tiago Fleming, Y1 - 2017/03/03/ PY - 2016/06/21/received PY - 2017/02/03/accepted PY - 2017/3/4/entrez PY - 2017/3/4/pubmed PY - 2017/6/20/medline SP - e2000374 EP - e2000374 JF - PLoS biology JO - PLoS Biol VL - 15 IS - 3 N2 - 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. SN - 1545-7885 UR - https://www.unboundmedicine.com/medline/citation/28257421/The_mechanism_of_sirtuin_2_mediated_exacerbation_of_alpha_synuclein_toxicity_in_models_of_Parkinson_disease_ L2 - https://dx.plos.org/10.1371/journal.pbio.2000374 DB - PRIME DP - Unbound Medicine ER -