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Local regulation of extracellular vesicle traffic by the synaptic endocytic machinery
Journal of Cell Biology ( IF 7.4 ) Pub Date : 2022-03-23 , DOI: 10.1083/jcb.202112094
Cassandra R Blanchette 1 , Amy L Scalera 1 , Kathryn P Harris 2, 3 , Zechuan Zhao 1 , Erica C Dresselhaus 1 , Kate Koles 1 , Anna Yeh 1 , Julia K Apiki 1 , Bryan A Stewart 2, 3 , Avital A Rodal 1
Affiliation  

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.

中文翻译:


突触内吞机制对细胞外囊泡运输的局部调节



神经元细胞外囊泡(EV)从突触前末梢局部释放,携带对细胞间信号传导和疾病至关重要的物质。 EV 源自内体,但尚不清楚这些货物如何定向至 EV 途径而不是进行传统的内溶酶体降解。在这里,我们发现内吞机制在维持突触处的 EV 货物的释放能力池中发挥着意想不到的作用。内吞突变体,包括神经残骸 (nwk)、shibire/dynamin 和 AP-2,出乎意料地表现出局部突触前耗竭,特别是 EV 货物。因此,nwk突变体表型突触可塑性缺陷与EV货物synaptotagmin-4(Syt4)的丢失相关,并抑制EV货物淀粉样前体蛋白(APP)过度表达时的致死率。这些 EV 缺陷在基因上与突触小泡回收和突触生长中的典型内吞功能是分离的。内吞机制对抗内体逆转录酶复合物来调节 EV 货物水平,并通过逆行轴突运输作用于突触货物去除的上游。我们的数据表明了一种新颖的分子机制,可以局部促进货物装载到突触电动汽车中。
更新日期:2022-03-23
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