Neddylation inhibition impairs spine development, destabilizes synapses and deteriorates cognition

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.Fil: Vogl, Annette M.. Instituto Max Planck de Psiquiatria de Munich; AlemaniaFil: Brockmann, Marisa M.. Instituto Max Planck de Psiquiatria de Munich; AlemaniaFil: Giusti, Sebastian Alejandro. Instituto Max Planck de Psiquiatria de Munich; Alemania. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: MacCarrone, Giuseppina. Instituto Max Planck de Psiquiatria de Munich; AlemaniaFil: Vercelli, Claudia Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; ArgentinaFil: Bauder, Corinna A.. Instituto Max Planck de Psiquiatria de Munich; AlemaniaFil: Richter, Julia S.. Instituto Max Planck de Psiquiatria de Munich; Alemania. Instituto Max Planck de Psiquiatria de Munich; AlemaniaFil: Roselli, Francesco. Universita Degli Studi Di Bari; ItaliaFil: Hafner, Anne-Sophie. Universite de Bordeaux; FranciaFil: Dedic, Nina. Instituto Max Planck de Psiquiatria de Munich; AlemaniaFil: Wotjak, Carsten T.. Instituto Max Planck de Psiquiatria de Munich; AlemaniaFil: Vogt Weisenhorn, Daniela M.. Institute Of Developmental Genetics; AlemaniaFil: Choquet, Daniel. Universite de Bordeaux; FranciaFil: Turck, Christoph W.. Instituto Max Planck de Psiquiatria de Munich; AlemaniaFil: Stein, Valentin. Universitaet Bonn; AlemaniaFil: Deussing, Jan M.. Instituto Max Planck de Psiquiatria de Munich; AlemaniaFil: Refojo, Damian. Instituto Max Planck de Psiquiatria de Munich; Alemani