Abstract
Mechanisms regulating the turnover of synaptic vesicle (SV) proteins are not well understood. They are thought to require poly-ubiquitination and degradation through proteasome, endo-lysosomal or autophagy-related pathways. Bassoon was shown to negatively regulate presynaptic autophagy in part by scaffolding Atg5. Here, we show that increased autophagy in Bassoon knockout neurons depends on poly-ubiquitination and that the loss of Bassoon leads to elevated levels of ubiquitinated synaptic proteins per se. Our data show that Bassoon knockout neurons have a smaller SV pool size and a higher turnover rate as indicated by a younger pool of SV2. The E3 ligase Parkin is required for increased autophagy in Bassoon-deficient neurons as the knockdown of Parkin normalized autophagy and SV protein levels and rescued impaired SV recycling. These data indicate that Bassoon is a key regulator of SV proteostasis and that Parkin is a key E3 ligase in the autophagy-mediated clearance of SV proteins.
Highlights
Presynaptic active zones, the sites of synaptic vesicle fusion, are comprised of a dense network of scaffold proteins
We investigate mechanisms regulating the turnover of synaptic vesicle (SV) proteins using the loss of the active zone (AZ) protein Bassoon as a driver of local autophagy (Okerlund et al, 2017)
Our data suggest that Bassoon negatively regulates ubiquitination of a number of SV proteins and that the enhanced ubiquitination of presynaptic proteins is a potent driver of presynaptic autophagy in Bsn-deficient neurons, leading to smaller pools of SVs with apparently younger proteins
Summary
Presynaptic active zones, the sites of synaptic vesicle fusion, are comprised of a dense network of scaffold proteins These function to coordinate the regulated release of neurotransmitters as well as the cellular machinery that maintains the function and integrity of presynaptic boutons and neuronal communication (Rangaraju et al, 2014; Wang et al, 2017). Recent studies point to the presence of several proteostatic mechanisms within or near synapses that function to remove non-functional and/or damaged proteins These include the proteasome, the endo-lysosomal system and autophagy (Hoffmann et al, 2019; Kaushik and Cuervo, 2015; Lazarevic et al, 2011; Vijayan and Verstreken, 2017; Wang et al, 2017).
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