The ubiquitin–proteasome system (UPS) is essential for the degradation of damaged proteins in eukaryotic cells. Although the general function of this system has been characterized in detail in many cell types, we don't know much about its role in neurons. Some reports have linked the UPS to conditions such as Parkinson's disease and Angelman's syndrome, and others have pointed to its direct involvement in synaptic plasticity. A recent paper by DiAntonio et al. raises the intriguing possibility that the UPS might participate in synaptic development in Drosophila.

The authors screened a collection of flies that overexpressed endogenous genes, looking for mutants in which the structure of the neuromuscular junction was abnormal. DiAntonio et al. observed that overexpression of fat facets ( faf ), a de-ubiquitinating protease that antagonizes the action of the UPS, led to synaptic overgrowth and diminished transmitter release. Moreover, the authors showed that overexpressing a de-ubiquitinating protease from yeast had a similar effect, indicating that synaptic growth and function do depend on the UPS.

What are the molecular pathways that are affected by faf? To answer this question, DiAntonio et al. searched for lethal enhancers of the phenotype and identified highwire ( hiw ). The hiw transcript encodes a putative member of the ubiquitin ligase family — proteins that transfer activated ubiquitin to abnormal proteins, targeting them for degradation. The phenotype of loss-of-function hiw mutants was similar to that observed in flies that overexpressed faf, pointing again to the involvement of the UPS system in synaptic development. Furthermore, the deficits in transmitter release, but not the morphological abnormalities, were partly rescued in loss-of-function hiw;faf double mutants. This observation indicates that the two phenotypes can be genetically dissociated, and that a balance between negative and positive regulators of the UPS controls synaptic function.

What are the synaptic substrates that are regulated by the UPS? Does a similar mechanism operate in other synapses and in other organisms? Is the UPS function important for short-term synaptic plasticity? Like every ground-breaking article, this paper poses more questions than it answers.