Department of Biology, Brandeis University, Waltham, MA.
J Cell Biol. 2021 Aug 2;220(8). doi: 10.1083/jcb.202012034. Epub 2021 May 21.
Neuronal extracellular vesicles (EVs) play important roles in intercellular communication and pathogenic protein propagation in neurological disease. However, it remains unclear how cargoes are selectively packaged into neuronal EVs. Here, we show that loss of the endosomal retromer complex leads to accumulation of EV cargoes including amyloid precursor protein (APP), synaptotagmin-4 (Syt4), and neuroglian (Nrg) at Drosophila motor neuron presynaptic terminals, resulting in increased release of these cargoes in EVs. By systematically exploring known retromer-dependent trafficking mechanisms, we show that EV regulation is separable from several previously identified roles of neuronal retromer. Conversely, mutations in rab11 and rab4, regulators of endosome-plasma membrane recycling, cause reduced EV cargo levels, and rab11 suppresses cargo accumulation in retromer mutants. Thus, EV traffic reflects a balance between Rab4/Rab11 recycling and retromer-dependent removal from EV precursor compartments. Our data shed light on previous studies implicating Rab11 and retromer in competing pathways in Alzheimer's disease, and suggest that misregulated EV traffic may be an underlying defect.
神经元细胞外囊泡 (EVs) 在神经疾病中的细胞间通讯和致病蛋白传播中发挥重要作用。然而，细胞外囊泡如何选择性地包装 cargoes 仍然不清楚。在这里，我们发现内体逆向转运复合物的缺失会导致包括淀粉样前体蛋白 (APP)、突触结合蛋白 4 (Syt4) 和神经胶质蛋白 (Nrg) 在内的 EV cargoes 在果蝇运动神经元突触前末端积累，导致这些 cargoes 在 EV 中的释放增加。通过系统地探索已知的逆向转运复合物依赖性运输机制，我们表明 EV 的调节与神经元逆向转运复合物的几个先前确定的作用是可分离的。相反，内体-质膜再循环的调节因子 rab11 和 rab4 的突变会导致 EV cargo 水平降低，并且 rab11 抑制逆向转运复合物突变体中 cargo 的积累。因此，EV 运输反映了 Rab4/Rab11 再循环和逆向转运复合物依赖性从 EV 前体隔室中去除之间的平衡。我们的数据阐明了先前的研究表明 Rab11 和逆向转运复合物在阿尔茨海默病中的竞争途径，并表明失调的 EV 运输可能是一个潜在的缺陷。
