title: The mechanism of sirtuin 2-mediated exacerbation of alpha-synuclein toxicity in models of Parkinson disease.
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.
authors.affiliation: CEDOC, NOVA Medical School, Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Lisboa, Portugal.
authors.forename: Rita Machado
authors.initials: RM
authors.lastname: de Oliveira
authors.affiliation: CEDOC, NOVA Medical School, Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Lisboa, Portugal.
authors.forename: Hugo
authors.identifier: 0000-0001-8065-9259
authors.initials: H
authors.lastname: Vicente Miranda
authors.affiliation: Department of Neurodegeneration and Restorative Research, University Medical Center Göttingen, Göttingen, Germany.
authors.forename: Laetitia
authors.initials: L
authors.lastname: Francelle
authors.affiliation: Department of Neurodegeneration and Restorative Research, University Medical Center Göttingen, Göttingen, Germany.|Faculty of Medicine, University of Porto, Porto, Portugal.
authors.forename: Raquel
authors.initials: R
authors.lastname: Pinho
authors.affiliation: Department of Neurodegeneration and Restorative Research, University Medical Center Göttingen, Göttingen, Germany.
authors.forename: Éva M
authors.initials: ÉM
authors.lastname: Szegö
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.
authors.forename: Renato
authors.initials: R
authors.lastname: Martinho
authors.affiliation: Department for NMR-based Structural Biology, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany.|German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany.
authors.forename: Francesca
authors.initials: F
authors.lastname: Munari
authors.affiliation: Department of Neurodegeneration and Restorative Research, University Medical Center Göttingen, Göttingen, Germany.
authors.forename: Diana F
authors.initials: DF
authors.lastname: Lázaro
authors.affiliation: Department of Biochemistry, University of Bayreuth, Bayreuth, Germany.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Moniot
authors.affiliation: Department of Neurodegeneration and Restorative Research, University Medical Center Göttingen, Göttingen, Germany.
authors.forename: Patrícia
authors.initials: P
authors.lastname: Guerreiro
authors.affiliation: Department for NMR-based Structural Biology, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany.
authors.forename: Luis
authors.initials: L
authors.lastname: Fonseca-Ornelas
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.
authors.forename: Zrinka
authors.initials: Z
authors.lastname: Marijanovic
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.
authors.forename: Pedro
authors.initials: P
authors.lastname: Antas
authors.affiliation: Department of Neurodegeneration and Restorative Research, University Medical Center Göttingen, Göttingen, Germany.
authors.forename: Ellen
authors.initials: E
authors.lastname: Gerhardt
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.
authors.forename: Francisco Javier
authors.initials: FJ
authors.lastname: Enguita
authors.affiliation: Laboratory of Molecular and Chemical Biology of Neurodegeneration, Swiss Federal Institute of Technology Lausanne (EPFL), Lausanne, Switzerland.
authors.forename: Bruno
authors.initials: B
authors.lastname: Fauvet
authors.affiliation: Laboratório de Proteómica, Departamento de Genética Humana, Instituto Nacional de Saúde Dr. Ricardo Jorge, Lisboa, Portugal.
authors.forename: Deborah
authors.initials: D
authors.lastname: Penque
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.
authors.forename: Teresa Faria
authors.initials: TF
authors.lastname: Pais
authors.affiliation: USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Tong
authors.affiliation: Department for NMR-based Structural Biology, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Becker
authors.affiliation: Department of Neurology, University Medical Center Göttingen, University of Göttingen, Göttingen, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Kügler
authors.affiliation: Laboratory of Molecular and Chemical Biology of Neurodegeneration, Swiss Federal Institute of Technology Lausanne (EPFL), Lausanne, Switzerland.
authors.forename: Hilal Ahmed
authors.initials: HA
authors.lastname: Lashuel
authors.affiliation: Department of Biochemistry, University of Bayreuth, Bayreuth, Germany.
authors.forename: Clemens
authors.initials: C
authors.lastname: Steegborn
authors.affiliation: 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.
authors.forename: Markus
authors.initials: M
authors.lastname: Zweckstetter
authors.affiliation: 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.
authors.forename: Tiago Fleming
authors.initials: TF
authors.lastname: Outeiro
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000107:Acetylation / Q000187:drug effects; D000818:Animals; D001343:Autophagy / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000473:pathology; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism; D017353:Gene Deletion; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D008239:Lysine / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D000066829:Neuroprotection / Q000187:drug effects; D010300:Parkinson Disease / Q000378:metabolism* / Q000473:pathology*; D066329:Protein Aggregates / Q000187:drug effects; D011485:Protein Binding; D056565:Sirtuin 2 / Q000378:metabolism*; D051844:alpha-Synuclein / Q000633:toxicity*
chemical_list: D066329:Protein Aggregates; D051844:alpha-Synuclein; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D056565:Sirtuin 2; D008239:Lysine