RT Journal Article
SR Electronic
T1 Local regulation of extracellular vesicle traffic by the synaptic endocytic machinery
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.08.04.454987
DO 10.1101/2021.08.04.454987
A1 Blanchette, Cassandra R.
A1 Scalera, Amy L.
A1 Harris, Kathryn P.
A1 Zhao, Zechuan
A1 Koles, Kate
A1 Yeh, Anna
A1 Apiki, Julia K.
A1 Stewart, Bryan A.
A1 Rodal, Avital A.
YR 2021
UL http://biorxiv.org/content/early/2021/09/07/2021.08.04.454987.abstract
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.