Neddylation is required for presynaptic clustering of mGlu7 and maturation of presynaptic terminals

Abstract

Neddylation is a posttranslational modification in which NEDD8 is conjugated to a target substrate by cellular processes similar to those involved in ubiquitination. Recent studies have identified PSD-95 and cofilin as substrates for neddylation in the brain and have shown that neddylation modulates the maturation and stability of dendritic spines in developing neurons. However, the precise substrates and functional consequences of neddylation at presynaptic terminals remain elusive. Here, we provide evidence that the mGlu7 receptor is a target of neddylation in heterologous cells and rat primary cultured neurons. We found that mGlu7 neddylation is reduced by agonist treatment and is required for the clustering of mGlu7 in the presynaptic active zone. In addition, we observed that neddylation is not required for the endocytosis of mGlu7, but it facilitates the ubiquitination of mGlu7 and stabilizes mGlu7 protein expression. Finally, we demonstrate that neddylation is necessary for the maturation of excitatory presynaptic terminals, providing a key role for neddylation in synaptic function.

Nervous system: Nerve cell development

New insights into the role of a regulatory protein in nerve development and activity in the brain will increase understanding of the maturation of nerve cells and the pathology of neurodevelopmental disorders. Young Ho Suh and colleagues at Seoul National University College of Medicine in South Korea studied cultured rat nerve cells to investigate a process called neddylation, mediated by the protein NEDD8. Neddylation occurs when NEDD8 is attached to other proteins in a manner that regulates the cell proliferation, but details of neddylation’s effects have been elusive in nerve cells. The authors have now identified a specific receptor protein in nerve cell membranes as a target for neddylation. This process seems to be required for the maturation and activity of nerve endings called pre-synapses, which release neurotransmitters to send signals to other nerve cells.