Ubiquitinylation an degradation of postsynaptic scaffold Proteins
In the mammalian brain, excitatory synapses are localized on the tip of dendritic protrusions called spines, which contain a membrane-associated protein network named postsynaptic density (PSD). Changes in the molecular composition of the PSD are fundamental to synaptic development and plasticity. The scaffold of the PSD constitutes of several multi-domain proteins, including different members of the Shank and SAPAP families. Neuronal activity induces degradation of selected PSD components by the ubiquitin/proteasome system (UPS), including Shank and SAPAP subtypes. Using in vivo stimulation protocols, we intend to analyze the kinetics and substrate specificity of UPS activity at postsynaptic sites in the rat brain. In vitro and cellular assays will be used to investigate the molecular mechanisms regulating ubiquitylation and proteasomal targeting of Shank and SAPAP family members. In particular we will attempt to identify proteins acting as ubiquitin ligases or proteasome adaptors for these postsynaptic proteins. The outlined research is intended to decipher the role of the UPS in activity-induced modulations of the synapse, which may contribute to learning and memory.