Molecular insights in the biogenesis and transport of presynaptic transport vesicles

Synapse formation, maintenance and function requires a continuous material supply from the neuronal soma, the site of protein production. Presynaptic material is suggested to traffic on highly specialised and diverse membranous organelles, the presynaptic precursor vesicles (reviewed in Petzoldt, Cells, 2023). Molecular mechanisms controlling their assembly and transport remain poorly understood. We could show that the small GTPase Rab2 is required in a Golgi-associated assembly sequence during early presynaptic precursor biogenesis (Götz … Sigrist, Petzoldt, JCB, 2021). Upon Rab2 depletion, both active zone and synaptic vesicle proteins accumulate at the trans-Golgi in the cell body in ectopic aggregates consistent of heterogeneous vesicles and short tubules of 40 × 60 nm size, likely immature precursor vesicles incompetent to leave the neuronal soma. Consequently, synaptic terminals are depleted of presynaptic material, provoking neurotransmission deficits. In preliminary experiments, we identified two novel Rab2 effector proteins acting at the trans-Golgi during precursor biogenesis, shedding light on the early Rab2-dependent formation steps of presynaptic transport vesicles. Supporting the recent discovery of our colleagues showing the requirement of the late endosomal signalling lipid phosphatidylinositol 3,5-bisphosphate [PI(3,5)P2] for the axonal transport of precursor vesicles in human neurons (Rizalar*, Lucht, Petzoldt et al., Science, 2023), we could confirm a similar requirement for [PI(3,5)P2] signalling through genetic inhibition of [PI(3,5)P2] synthesis by PIKFYVE (Fab1 in Drosophila) knockdown in invertebrates and the independency of precursor vesicle transport of the lysosomal BORC-complex, shaping a model of conserved mechanisms of presynaptic precursor biogenesis and transport across species.