Neddylation inhibition impairs spine development, destabilizes synapses and deteriorates cognition

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Behavior, Animal / physiology
  • Brain / growth & development*
  • Brain / metabolism
  • Cognition Disorders / metabolism*
  • Dendritic Spines / physiology*
  • Disks Large Homolog 4 Protein
  • Guanylate Kinases / physiology*
  • Membrane Proteins / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NEDD8 Protein
  • Rats
  • Rats, Sprague-Dawley
  • Synapses / physiology*
  • Synaptic Transmission / physiology*
  • Ubiquitin-Activating Enzymes / genetics
  • Ubiquitin-Activating Enzymes / physiology
  • Ubiquitins / antagonists & inhibitors
  • Ubiquitins / metabolism*


  • Disks Large Homolog 4 Protein
  • Dlg4 protein, mouse
  • Membrane Proteins
  • NEDD8 Protein
  • Nedd8 protein, mouse
  • Nedd8-activating enzyme E1 protein, mouse
  • Ubiquitins
  • Guanylate Kinases
  • Ubiquitin-Activating Enzymes