Dresselhaus Erica C, Harris Kathryn P, Blanchette Cassandra R, Koles Kate, Del Signore Steven J, Pescosolido Matthew F, Ermanoska Biljana, Rozencwaig Mark, Soslowsky Rebecca C, Parisi Michael J, Stewart Bryan A, Mosca Timothy J, Rodal Avital A
Department of Biology, Brandeis University, Waltham, MA.
Office of the Vice-Principal, Research and Innovation, University of Toronto, Mississauga, Mississauga, Canada.
bioRxiv. 2024 May 5:2023.04.22.537920. doi: 10.1101/2023.04.22.537920.
Extracellular vesicles (EVs) are released by many cell types including neurons, carrying cargoes involved in signaling and disease. It is unclear whether EVs promote intercellular signaling or serve primarily to dispose of unwanted materials. We show that loss of multivesicular endosome-generating ESCRT (endosomal sorting complex required for transport) machinery disrupts release of EV cargoes from motor neurons. Surprisingly, ESCRT depletion does not affect the signaling activities of the EV cargo Synaptotagmin-4 (Syt4) and disrupts only some signaling activities of the EV cargo Evenness Interrupted (Evi). Thus, these cargoes may not require intercellular transfer via EVs, and instead may be conventionally secreted or function cell autonomously in the neuron. We find that EVs are phagocytosed by glia and muscles, and that ESCRT disruption causes compensatory autophagy in presynaptic neurons, suggesting that EVs are one of several redundant mechanisms to remove cargoes from synapses. Our results suggest that synaptic EV release serves primarily as a proteostatic mechanism for certain cargoes.
细胞外囊泡（EVs）由包括神经元在内的多种细胞类型释放，携带参与信号传导和疾病的物质。目前尚不清楚细胞外囊泡是促进细胞间信号传导，还是主要用于处理不需要的物质。我们发现，产生多囊泡内体的ESCRT（转运所需的内体分选复合物）机制的缺失会破坏运动神经元释放细胞外囊泡中的物质。令人惊讶的是，ESCRT的缺失并不影响细胞外囊泡物质突触结合蛋白-4（Syt4）的信号传导活性，仅破坏细胞外囊泡物质Evenness Interrupted（Evi）的一些信号传导活性。因此，这些物质可能不需要通过细胞外囊泡进行细胞间转移，而是可能通过常规分泌或在神经元中自主发挥作用。我们发现，细胞外囊泡被神经胶质细胞和肌肉吞噬，并且ESCRT破坏会导致突触前神经元出现代偿性自噬，这表明细胞外囊泡是从突触清除物质的几种冗余机制之一。我们的结果表明，突触细胞外囊泡释放主要作为某些物质的蛋白质稳态机制。
