Neddylation inhibition impairs spine development, destabilizes synapses and 
deteriorates cognition

Vogl, Annette M.; Brockmann, Marisa M.; Giusti, Sebastian A.; Maccarrone, Giuseppina; Vercelli, Claudia A.; Bauder, Corinna A.; Richter, Julia S.; Roselli, Francesco; Hafner, Anne-Sophie; Dedic, Nina; Wotjak, Carsten T.; Vogt-Weisenhorn, Daniela M.; Choquet, Daniel; Turck, Christoph W.; Stein, Valentin; Deussing, Jan M.; Refojo, Damian

doi:10.1038/nn.3912

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Neddylation inhibition impairs spine development, destabilizes synapses and deteriorates cognition

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Vogl, Annette M.
Max Planck Research Group Molecular Neurobiology (Damian Refojo), Max Planck Institute of Psychiatry, Max Planck Society;

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Brockmann, Marisa M.
Max Planck Research Group Molecular Neurobiology (Damian Refojo), Max Planck Institute of Psychiatry, Max Planck Society;

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Giusti, Sebastian A.
Max Planck Research Group Molecular Neurobiology (Damian Refojo), Max Planck Institute of Psychiatry, Max Planck Society;

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Maccarrone, Giuseppina
Dept. Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;

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Bauder, Corinna A.
Max Planck Research Group Molecular Neurobiology (Damian Refojo), Max Planck Institute of Psychiatry, Max Planck Society;

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Richter, Julia S.
Max Planck Research Group Molecular Neurobiology (Damian Refojo), Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons80298

Dedic, Nina
Dept. Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Max Planck Society;

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Wotjak, Carsten T.
Dept. Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Max Planck Society;

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Turck, Christoph W.
Dept. Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;

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Refojo, Damian
Max Planck Research Group Molecular Neurobiology (Damian Refojo), Max Planck Institute of Psychiatry, Max Planck Society;

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Citation

Vogl, A. M., Brockmann, M. M., Giusti, S. A., Maccarrone, G., Vercelli, C. A., Bauder, C. A., et al. (2015). Neddylation inhibition impairs spine development, destabilizes synapses and deteriorates cognition. NATURE NEUROSCIENCE, 18(2), 239-251. doi:10.1038/nn.3912.

Cite as: https://hdl.handle.net/11858/00-001M-0000-0028-FF9F-B

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(CamKll alpha-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.