Soma-localized Rab39 inhibits synaptic autophagy by controlling trafficking of Atg9 vesicles

Presynaptic terminals can be located far from the neuronal cell body and are thought to independently regulate protein and organelle turnover. Autophagy is a critical process for maintaining proteostasis, and its synaptic dysregulation is associated with neurodegenerative diseases. In this work, we report a soma-centered mechanism that regulates autophagy-controlled protein turnover at distant presynaptic terminals in Drosophila. We show that a central component of this system is Rab39, whose human homolog RAB39B is mutated in Parkinson's disease. Although Rab39 is localized in the soma, its loss of function or a human pathogenic mutation causes increased autophagy at presynaptic terminals, resulting in faster synaptic protein turnover and dopaminergic synapse degeneration. Using a large-scale unbiased genetic modifier screen, we identified genes encoding cytoskeletal and axonal organizing proteins, including Shortstop (Shot), as suppressors of synaptic autophagy. We demonstrate that active Rab39 selectively controls Shot- and Unc104/KIF1A-mediated delivery of autophagy-related Atg9-positive vesicles to synapses. Our findings suggest that Rab39-mediated trafficking in the soma orchestrates a cross-compartmental mechanism that regulates the levels of autophagy at synapses.