Neddylation inhibition impairs spine development, destabilizes synapses and deteriorates cognition.

Annette M Vogl, Marisa M Brockmann, Sebastian A Giusti, Giuseppina Maccarrone, Claudia A Vercelli, Corinna A Bauder, Julia S Richter, Francesco Roselli, Anne-Sophie Hafner, Nina Dedic, Carsten T Wotjak, Daniela M Vogt-Weisenhorn, Daniel Choquet, Christoph W Turck, Valentin Stein, Jan M Deussing, Damian Refojo
Nat Neurosci. 2015-01-12; 18(2): 239-251
DOI: 10.1038/nn.3912

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1. Nat Neurosci. 2015 Feb;18(2):239-51. doi: 10.1038/nn.3912. Epub 2015 Jan 12.

Neddylation inhibition impairs spine development, destabilizes synapses and
deteriorates cognition.

Vogl AM(1), Brockmann MM(1), Giusti SA(1), Maccarrone G(2), Vercelli CA(3),
Bauder CA(1), Richter JS(1), Roselli F(4), Hafner AS(5), Dedic N(6), Wotjak
CT(7), Vogt-Weisenhorn DM(8), Choquet D(5), Turck CW(2), Stein V(9), Deussing
JM(7), Refojo D(1).

Author information:
(1)Molecular Neurobiology, Max Planck Institute of Psychiatry, Munich, Germany.
(2)Department for Translational Research in Psychiatry, Max Planck Institute of
Psychiatry, Munich, Germany.
(3)Instituto de Investigación en Biomedicina de Buenos Aires
(IBioBA)-CONICET-Partner Institute of the Max Planck Society, Buenos Aires,
Argentina.
(4)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.
(5)1] University of Bordeaux, Interdisciplinary Institute for Neuroscience,
Bordeaux, France. [2] CNRS UMR 5297, Bordeaux, France.
(6)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.
(7)Department of Neurobiology of Stress and Neurogenetics, Max Planck Institute
of Psychiatry, Munich, Germany.
(8)Institute of Developmental Genetics, Helmholtz-Zentrum München, Neuherberg,
Germany.
(9)Institute of Physiology, University of Bonn, Bonn, Germany.

Comment in
Nat Neurosci. 2015 Feb;18(2):164-6.

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.

DOI: 10.1038/nn.3912
PMID: 25581363 [Indexed for MEDLINE]


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