Control of protein degradation at synapses – COPRODS

The regulation of proteostasis at synapses is essential for synapse formation, function and plasticity. Deficiencies in this process have been associated with neurodevelopmental disorders. Proteostasis involves the regulation of protein synthesis, trafficking and degradation. Ubiquitination is a key posttranslational modification for the regulation of protein trafficking and degradation. In neurons, protein degradation needs to be controlled in an activity-dependent, synapse-specific and target-specific manner for proper circuit function and plasticity. For this, a solution would be the use of adaptor proteins capable of modulating ubiquitination and degradation pathways and whose activity and localization can be regulated in response to neural activity. However, the identities of these adaptor proteins and their regulation in neurons remain largely unknown.
The specific objectives of the project are to 1) provide a comprehensive analysis of the activity-dependent control of protein ubiquitination and degradation at synapses, and their dependence on NEDD4 ubiquitin ligases and a potential transmembrane adaptor identified by the consortium; 2) analyse the activity-dependent targeting of the degradation machinery in dendritic spines; 3) explore the potential extracellular control of the ubiquitination and degradation machinery at synapses.
Thanks to the complementary expertise of three research teams (Selimi, Letellier, and Elegheert), a multidisciplinary approach will be used combining biochemistry, dynamic analysis of synaptic proteins and super-resolution imaging, neuron-specific genetic tools and functional analysis in the mouse.