Historical perspective and progress on protein ubiquitination at glutamatergic synapses.

Abstract Transcription-translation coupling leads to the production of proteins that are key for controlling essential neuronal processes that include neuronal development and changes in synaptic strength. Although these events have been a prevailing theme in neuroscience, the regulation of proteins via posttranslational signaling pathways are equally relevant for these neuronal processes. Ubiquitin is one type of posttranslational modification that covalently attaches to its targets/substrates. Ubiquitination of proteins play a key role in multiple signaling pathways, the predominant being removal of its substrates by a large molecular machine called the proteasome. Here, I review 40 years of progress on ubiquitination in the nervous system at glutamatergic synapses focusing on axon pathfinding, synapse formation, presynaptic release, dendritic spine formation, and regulation of postsynaptic glutamate receptors. Finally, I elucidate emerging themes in ubiquitin biology that may challenge our current understanding of ubiquitin signaling in the nervous system.