Local 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 degr...

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Bibliographic Details
Published in:The Journal of cell biology 2022-05, Vol.221 (5), p.1
Main Authors: Blanchette, Cassandra R, Scalera, Amy L, Harris, Kathryn P, Zhao, Zechuan, Dresselhaus, Erica C, Koles, Kate, Yeh, Anna, Apiki, Julia K, Stewart, Bryan A, Rodal, Avital A
Format: Article
Language:English
Subjects:
Alzheimer's disease
Amyloid precursor protein
Axonal transport
Defects
Depletion
Dynamin
Endosomes
Extracellular Vesicles - metabolism
Genetics
Lethality
Mutants
Neuroscience
Organelles
Presynaptic Terminals - metabolism
Synapses
Synapses - metabolism
Synaptic plasticity
Synaptic Vesicles - metabolism
Synaptogenesis
Synaptotagmin
Trafficking
Transport buildings, stations and terminals
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Summary: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 protein (APP). These EV defects are genetically separable from canonical endocytic functions in synaptic vesicle recycling and synaptic growth. Endocytic machinery 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 locally promotes cargo loading into synaptic EVs.
ISSN:0021-9525
1540-8140
1540-8140
DOI:10.1083/jcb.202112094