title: Neddylation inhibition impairs spine development, destabilizes synapses and deteriorates cognition.
abstract: Neddylation is a ubiquitylation-like pathway that controls cell cycle and proliferation by covalently conjugating Nedd8 to specific targets. However, its role in neurons, nonreplicating postmitotic cells, remains unexplored. Here we report that Nedd8 conjugation increased during postnatal brain development and is active in mature synapses, where many proteins are neddylated. We show that neddylation controls spine development during neuronal maturation and spine stability in mature neurons. We found that neddylated PSD-95 was present in spines and that neddylation on Lys202 of PSD-95 is required for the proactive role of the scaffolding protein in spine maturation and synaptic transmission. Finally, we developed Nae1(CamKIIα-CreERT2) mice, in which neddylation is conditionally ablated in adult excitatory forebrain neurons. These mice showed synaptic loss, impaired neurotransmission and severe cognitive deficits. In summary, our results establish neddylation as an active post-translational modification in the synapse regulating the maturation, stability and function of dendritic spines.
authors.affiliation: Molecular Neurobiology, Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: Annette M
authors.initials: AM
authors.lastname: Vogl
authors.affiliation: Molecular Neurobiology, Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: Marisa M
authors.initials: MM
authors.lastname: Brockmann
authors.affiliation: Molecular Neurobiology, Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: Sebastian A
authors.initials: SA
authors.lastname: Giusti
authors.affiliation: Department for Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Maccarrone
authors.affiliation: Instituto de Investigación en Biomedicina de Buenos Aires (IBioBA)-CONICET-Partner Institute of the Max Planck Society, Buenos Aires, Argentina.
authors.forename: Claudia A
authors.initials: CA
authors.lastname: Vercelli
authors.affiliation: Molecular Neurobiology, Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: Corinna A
authors.initials: CA
authors.lastname: Bauder
authors.affiliation: Molecular Neurobiology, Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: Julia S
authors.initials: JS
authors.lastname: Richter
authors.affiliation: 1] Department of Neurobiology of Stress and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany. [2] Department of Neuroscience, Section of Neurology, University of Bari, Bari, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Roselli
authors.affiliation: 1] University of Bordeaux, Interdisciplinary Institute for Neuroscience, Bordeaux, France. [2] CNRS UMR 5297, Bordeaux, France.
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Hafner
authors.affiliation: 1] Department of Neurobiology of Stress and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany. [2] Institute of Developmental Genetics, Helmholtz-Zentrum München, Neuherberg, Germany.
authors.forename: Nina
authors.initials: N
authors.lastname: Dedic
authors.affiliation: Department of Neurobiology of Stress and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: Carsten T
authors.initials: CT
authors.lastname: Wotjak
authors.affiliation: Institute of Developmental Genetics, Helmholtz-Zentrum München, Neuherberg, Germany.
authors.forename: Daniela M
authors.initials: DM
authors.lastname: Vogt-Weisenhorn
authors.affiliation: 1] University of Bordeaux, Interdisciplinary Institute for Neuroscience, Bordeaux, France. [2] CNRS UMR 5297, Bordeaux, France.
authors.forename: Daniel
authors.initials: D
authors.lastname: Choquet
authors.affiliation: Department for Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: Christoph W
authors.initials: CW
authors.lastname: Turck
authors.affiliation: Institute of Physiology, University of Bonn, Bonn, Germany.
authors.forename: Valentin
authors.initials: V
authors.lastname: Stein
authors.affiliation: Department of Neurobiology of Stress and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: Jan M
authors.initials: JM
authors.lastname: Deussing
authors.affiliation: Molecular Neurobiology, Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: Damian
authors.initials: D
authors.lastname: Refojo
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D001921:Brain / Q000254:growth & development* / Q000378:metabolism; D003072:Cognition Disorders / Q000378:metabolism*; D049229:Dendritic Spines / Q000502:physiology*; D000076122:Disks Large Homolog 4 Protein; D051528:Guanylate Kinases / Q000502:physiology*; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000075687:NEDD8 Protein; D051381:Rats; D017207:Rats, Sprague-Dawley; D013569:Synapses / Q000502:physiology*; D009435:Synaptic Transmission / Q000502:physiology*; D044764:Ubiquitin-Activating Enzymes / Q000235:genetics / Q000502:physiology; D014452:Ubiquitins / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; D008565:Membrane Proteins; D000075687:NEDD8 Protein; C513172:Nedd8 protein, mouse; C583290:Nedd8-activating enzyme E1 protein, mouse; D014452:Ubiquitins; D051528:Guanylate Kinases; D044764:Ubiquitin-Activating Enzymes