PT  - JOURNAL ARTICLE
AU  - Blanchette, Cassandra R.
AU  - Scalera, Amy L.
AU  - Harris, Kathryn P.
AU  - Zhao, Zechuan
AU  - Koles, Kate
AU  - Yeh, Anna
AU  - Apiki, Julia K.
AU  - Stewart, Bryan A.
AU  - Rodal, Avital A.
TI  - Local regulation of extracellular vesicle traffic by the synaptic endocytic machinery
AID  - 10.1101/2021.08.04.454987
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.08.04.454987
4099  - http://biorxiv.org/content/early/2021/09/07/2021.08.04.454987.short
4100  - http://biorxiv.org/content/early/2021/09/07/2021.08.04.454987.full
AB  - Neuronal extracellular vesicles (EVs) can be locally released from presynaptic terminals, carrying cargoes that are important in intercellular signaling and disease. EVs are derived from endosomes, but it remains unclear how synaptic cargoes are directed to the EV pathway, rather than undergoing conventional retrograde endosomal transport and degradation. Here, we find that the clathrin-mediated endocytic machinery plays an unexpected role in maintaining a release-competent pool of synaptic EV cargoes. Endocytic mutants, including nervous wreck (nwk), Shibire/Dynamin, and AP-2, exhibit local depletion of multiple cargoes in EV donor terminals. 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. This endocytic pathway opposes the endosomal retromer complex to regulate EV cargo levels, and acts upstream of synaptic cargo removal by retrograde axonal transport. Our data suggest a novel molecular mechanism that protects EV cargoes from local depletion at synapses.Competing Interest StatementThe authors have declared no competing interest.