Synaptic requiem: a duet for Piccolo and Bassoon.

Neurotransmission in the brain critically depends on the maintenance of synapses as well as on regulated synaptic protein turnover. How synaptic proteostasis is held in check has remained largely enigmatic. A new paper in The EMBO Journal reports that the active zone proteins Piccolo and Bassoon put a brake on presynaptic protein turnover by restraining the activity of the E3 ubiquitin ligase Siah1, thereby preventing neurodegeneration. To retain memories, neurons have evolved mechanisms of activity-dependent plasticity that involve remodelling of the synaptic proteome in response to internal or external cues. For example, the rapid re-organization of proteins at synaptic release sites, termed as active zones (AZ), may be utilized for the activity-dependent modulation of neurotransmission. Several mechanisms have been proposed for synaptic protein turnover, including local protein synthesis and degradation. Considerable attention has been paid to protein synthesis (Martin et al, 1997; Steward and Schuman, 2001), whereas the contributions of regulated protein turnover by the ubiquitin–proteasome system (UPS) or by the autophagylysosomal pathway to the regulation of synaptic efficacy are much less well understood. The current view suggests that the abundance of major synaptic proteins is controlled via a tightly controlled cascade of enzymes involved in the ubiquitination of protein substrates and their subsequent degradation by the 26S proteasome and/or by the autophagylysosomal pathway. Although a requirement for ubiquitin and the proteasome in neuronal function has been demonstrated (McNaught et al, 2001; Wilson et al, 2002), the molecular mechanisms underlying regulated synaptic protein turnover remain unclear. Almost a decade ago, Speese et al (2003) identified Drosophila UNC-13 (Dunc13), one of the core components of the AZ, as an acutely regulated UPS substrate in the presynaptic terminal. In this issue, Waites et al (2013) now report that two other core components of the AZ, Piccolo and Bassoon, have a role in regulating presynaptic ubiquitination and proteostasis. Piccolo and Bassoon are two giant vertebrate-specific AZ proteins whose precise role at the presynapse has remained somewhat enigmatic. Earlier work based on hypomorphic Piccolo/Bassoon-deficient mice had suggested a regulatory role for Piccolo/Bassoon in synaptic vesicle (SV) organization (Mukherjee et al, 2010), though the defects reported were surprisingly mild. Garner and colleagues Post-synapse PSD Pre-synapse SVP Bassoon/Piccolo knockdown