Local regulation of extracellular vesicle traffic by the synaptic endocytic machinery

Abstract

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.

Emerging Roles of Neuronal Extracellular Vesicles at the Synapse

“…To answer this question in neurons, the Drosophila neuromuscular junction (NMJ) has proven to be a powerful model system to study the secretion and cargo sorting that occur at the presynaptic terminal. In addition to canonical neurotransmitter release, the presynaptic terminal releases EVs containing cargoes such as tetraspanins, synaptotagmin 4 (Syt-4), neuroglian (Nrg), amyloid precursor protein (APP), and evenness interrupted (Evi) (Blanchette and others 2022; Korkut and others 2013; Walsh and others 2021). In this system, secretion can be clearly visualized in the whole tissue since secreted cargos are trapped in the extrasynaptic space and apposing muscle cells.…”

The evolving role of extracellular vesicles (exosomes) as biomarkers in traumatic brain injury: Clinical perspectives and therapeutic implications

“…A common element in EV-mediated neuron–glia communication is that EV release seems to be linked with synaptic activity (Frühbeis et al, 2013a ; Chivet et al, 2014 ; Fröhlich et al, 2014 ; Laulagnier et al, 2017 ). Emerging data suggest that the relationship between neuronal EVs discharge and synaptic activity may be important for the maintenance of plasticity, implying that neuronal EVs might influence synaptic plasticity and play an important role in maintaining neurovascular integrity (Korkut et al, 2013 ; Krämer-Albers and Hill, 2016 ; Blanchette et al, 2022 ). The trafficking of certain RNAs into EVs appears to have a function, such as the maintenance of synaptic plasticity and its association with local protein synthesis (Goldie et al, 2014 ; Anakor et al, 2021 ).…”

Quantitative mapping of synaptic periactive zone architecture and organization

“…Does stronger Dyn accumulation in the PAZ core reflect its roles in modes of endocytosis that occur proximal to release sites, including ultrafast endocytosis (Kidokoro, 2006;Koenig and Ikeda, 1996;Kosaka and Ikeda, 1983;Kuromi et al, 2010;Teng and Wilkinson, 2000;Watanabe et al, 2013a)? Are more peripheral PAZ proteins held in a 'poised' or inactive state, or are they engaged in more diverse synaptic functions beyond synaptic vesicle endocytosis (Blanchette et al, 2022;Gimber et al, 2015;Jäpel et al, 2020;O'Connor-Giles et al, 2008;Rodal et al, 2011Rodal et al, , 2008? Alternatively, this heterogeneity could also reflect different temporal stages of a single biological process (such as stages of endocytosis).…”

“…They are especially interesting to consider as PAZ constituents because they regulate endocytosis and synaptic vesicle trafficking (Dagar et al, 2021;Leshchyns'ka et al, 2006;Luo et al, 2021;Shetty et al, 2013;van Stegen et al, 2017), and are themselves endocytic cargoes. Indeed, presynaptic endocytosis and trafficking pathways regulate the levels and function of adhesion molecules (Bailey et al, 1992;Blanchette et al, 2022;Fu and Huang, 2010;Kurshan et al, 2018;Nahm et al, 2016;Yamada et al, 2007). Therefore, in addition to being important components of the PAZ, adhesion molecules are crucial regulators and effectors of the endocytic machinery at the synapse.…”