Neddylation inhibition impairs spine development, destabilizes synapses and deteriorates cognition
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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.
in: NAT NEUROSCI, Jahrgang 18, Nr. 2, 02.2015, S. 239-51.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Neddylation inhibition impairs spine development, destabilizes synapses and deteriorates cognition
AU - Vogl, Annette M
AU - Brockmann, Marisa M
AU - Giusti, Sebastian A
AU - Maccarrone, Giuseppina
AU - Vercelli, Claudia A
AU - Bauder, Corinna A
AU - Richter, Julia S
AU - Roselli, Francesco
AU - Hafner, Anne-Sophie
AU - Dedic, Nina
AU - Wotjak, Carsten T
AU - Vogt-Weisenhorn, Daniela M
AU - Choquet, Daniel
AU - Turck, Christoph W
AU - Stein, Valentin
AU - Deussing, Jan M
AU - Refojo, Damian
PY - 2015/2
Y1 - 2015/2
N2 - 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.
AB - 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.
KW - Animals
KW - Behavior, Animal/physiology
KW - Brain/growth & development
KW - Cognition Disorders/metabolism
KW - Dendritic Spines/physiology
KW - Disks Large Homolog 4 Protein
KW - Guanylate Kinases/physiology
KW - Membrane Proteins/physiology
KW - Mice
KW - Mice, Inbred C57BL
KW - Mice, Knockout
KW - NEDD8 Protein
KW - Rats
KW - Rats, Sprague-Dawley
KW - Synapses/physiology
KW - Synaptic Transmission/physiology
KW - Ubiquitin-Activating Enzymes/genetics
KW - Ubiquitins/antagonists & inhibitors
U2 - 10.1038/nn.3912
DO - 10.1038/nn.3912
M3 - SCORING: Journal article
C2 - 25581363
VL - 18
SP - 239
EP - 251
JO - NAT NEUROSCI
JF - NAT NEUROSCI
SN - 1097-6256
IS - 2
ER -