Abstract
Neuronal extracellular vesicles (EVs) carry cargoes that are important in intercellular signaling and disease, but how and where cargoes are sorted into EVs remains unclear. Here, we identified a new role for canonical clathrin-mediated endocytic machinery in controlling EV cargo traffic in Drosophila neurons. Endocytic mutants, including nervous wreck (nwk), Shibire/Dynamin, and AP-2, exhibit local depletion of multiple cargoes in presynaptic EV donor terminals as well as in EVs. Accordingly, nwk mutants phenocopy synaptic plasticity defects associated with loss of the EV cargo Synaptotagmin-4, and suppress lethality upon overexpression of the EV cargo Amyloid Precursor Protein. These EV defects are genetically separable from canonical functions of endocytic proteins in synaptic vesicle recycling and synaptic growth. Nwk opposes the endosomal retromer complex to regulate EV cargo levels, and acts upstream of dynactin-mediated retrograde axonal transport. Our data suggest a novel molecular mechanism that protects EV cargoes from local depletion at synapses.
Competing Interest Statement
The authors have declared no competing interest.
