Condensate biology of synaptic vesicle clusters.

Synapsins form fluid-like condensates enriched with synaptic vesicles (SVs). The intrinsically disordered region of synapsin is necessary and sufficient for the formation of vesicle condensates. The stoichiometry of synapsins and synucleins, two highly abundant synaptic proteins, is crucial for maintaining the architecture of SV condensates. Synapsin-driven condensates are reversible upon phosphorylation. Membrane properties and integral proteins of SVs drive the recruitment of vesicles into the phase and determine the motility of SVs between neighboring boutons. Neuronal communication crucially relies on exocytosis of neurotransmitters from synaptic vesicles (SVs) which are clustered at synapses. To ensure reliable neurotransmitter release, synapses need to maintain an adequate pool of SVs at all times. Decades of research have established that SVs are clustered by synapsin 1, an abundant SV-associated phosphoprotein. The classical view postulates that SVs are crosslinked in a scaffold of protein–protein interactions between synapsins and their binding partners. Recent studies have shown that synapsins cluster SVs via liquid–liquid phase separation (LLPS), thus providing a new framework for the organization of the synapse. We discuss the evidence for phase separation of SVs, emphasizing emerging questions related to its regulation, specificity, and reversibility. [ABSTRACT FROM AUTHOR]