biostudies-literatureBlanchette CRNational Institute of Neurological Disorders and StrokeNatural Sciences and Engineering Research Council of CanadaNIMH NIH HHSNINDS NIH HHSe202112094https://www.ebi.ac.uk/biostudies/studies/S-EPMC8952828biostudies-literatureUnknown221(5)Neuronal extracellular vesicles (EVs) are locally released from presynaptic terminals, carrying cargoes critical for intercellular signaling and disease. EVs are derived from endosomes, but it is unknown how these cargoes are directed to the EV pathway rather than for conventional endolysosomal degradation. Here, we find that endocytic machinery plays an unexpected role in maintaining a release-competent pool of EV cargoes at synapses. Endocytic mutants, including nervous wreck (nwk), shibire/dynamin, and AP-2, unexpectedly exhibit local presynaptic depletion specifically of EV cargoes. Accordingly, nwk mutants phenocopy synaptic plasticity defects associated with loss of the EV cargo synaptotagmin-4 (Syt4) and suppress lethality upon overexpression of the EV cargo amyloid precursor proteiThe Journal of cell biologyLocal regulation of extracellular vesicle traffic by the synaptic endocytic machinery.PMC8952828T32 MH019929T32 NS007292F32 NS110123RGPIN-06004R01 NS103967F32 NS120909Stewart BAScalera ALYeh ABlanchette CRDresselhaus ECZhao ZHarris KPApiki JKKoles KRodal AAfalseLocal regulation of extracellular vesicle traffic by the synaptic endocytic machinery.Neuronal extracellular vesicles (EVs) are locally released from presynaptic terminals, carrying cargoes critical for intercellular signaling and disease. EVs are derived from endosomes, but it is unknown how these cargoes are directed to the EV pathway rather than for conventional endolysosomal degradation. Here, we find that endocytic machinery plays an unexpected role in maintaining a release-competent pool of EV cargoes at synapses. Endocytic mutants, including nervous wreck (nwk), shibire/dynamin, and AP-2, unexpectedly exhibit local presynaptic depletion specifically of EV cargoes. Accordingly, nwk mutants phenocopy synaptic plasticity defects associated with loss of the EV cargo synaptotagmin-4 (Syt4) and suppress lethality upon overexpression of the EV cargo amyloid precursor protei2022-01-01T00:00:00Z2022 May2025-04-19T03:31:45.735Z2025-04-07T13:41:52.625ZS-EPMC89528283532034910.1083/jcb.202112094