Bassoon and piccolo regulate ubiquitination and link presynaptic molecular dynamics with activity-regulated gene expression

Abstract

Release of neurotransmitter is executed by complex multiprotein machinery, which is assembled around the presynaptic cytomatrix at the active zone. One well-established function of this proteinaceous scaffold is the spatial organization of synaptic vesicle cluster, the protein complexes that execute membrane fusion and compensatory endocytosis, and the transmembrane molecules important for alignment of pre- and postsynaptic structures. The presynaptic cytomatrix proteins function also in processes other than the formation of a static frame for assembly of the release apparatus and synaptic vesicle cycling. They actively contribute to the regulation of multiple steps in this process and are themselves an important subject of regulation during neuronal plasticity. We are only beginning to understand the mechanisms and signaling pathways controlling these regulations. They are mainly dependent on posttranslational modifications including phosphorylation and small-molecules conjugation, such as ubiquitination. Ubiquitination of presynaptic proteins might lead to their degradation by proteasome, but evidence is growing that this modification also affects their function independently of their degradation. Signaling from presynapse to nucleus, which works on much slower time scale and more globally, emerged as an important mechanism for persistent usage-dependent and homeostatic neuronal plasticity. Recently, two new functions for the largest presynaptic scaffolding proteins bassoon and piccolo emerged. They were implied 1) in the regulation of specific protein ubiquitination and proteasome-mediated proteolysis that potentially contributes to short-term plasticity at presynapse and 2) in the coupling of activity-induced molecular rearrangements at presynapse with reprograming of expression of neuronal activity-regulated genes.

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