Pinto Maria J, Alves Pedro L, Martins Luís, Pedro Joana R, Ryu Hyun R, Jeon Noo Li, Taylor Anne M, Almeida Ramiro D
CNC - Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal PhD Program in Experimental Biology and Biomedicine, Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal.
Instituto de Educação e Cidadania, 3770-033 Mamarrosa, Portugal.
J Cell Biol. 2016 Mar 28;212(7):789-801. doi: 10.1083/jcb.201509039.
Differentiation of the presynaptic terminal is a complex and rapid event that normally occurs in spatially specific axonal regions distant from the soma; thus, it is believed to be dependent on intra-axonal mechanisms. However, the full nature of the local events governing presynaptic assembly remains unknown. Herein, we investigated the involvement of the ubiquitin-proteasome system (UPS), the major degradative pathway, in the local modulation of presynaptic differentiation. We found that proteasome inhibition has a synaptogenic effect on isolated axons. In addition, formation of a stable cluster of synaptic vesicles onto a postsynaptic partner occurs in parallel to an on-site decrease in proteasome degradation. Accumulation of ubiquitinated proteins at nascent sites is a local trigger for presynaptic clustering. Finally, proteasome-related ubiquitin chains (K11 and K48) function as signals for the assembly of presynaptic terminals. Collectively, we propose a new axon-intrinsic mechanism for presynaptic assembly through local UPS inhibition. Subsequent on-site accumulation of proteins in their polyubiquitinated state triggers formation of presynapses.
突触前终末的分化是一个复杂且迅速的过程，通常发生在远离胞体的特定轴突区域；因此，人们认为它依赖于轴突内机制。然而，调控突触前组装的局部事件的全貌仍不清楚。在此，我们研究了主要降解途径泛素 - 蛋白酶体系统（UPS）在突触前分化的局部调节中的作用。我们发现蛋白酶体抑制对分离的轴突具有促突触形成的作用。此外，突触小泡在突触后伙伴上形成稳定簇的过程与蛋白酶体降解的局部减少同时发生。新生部位泛素化蛋白的积累是突触前簇集的局部触发因素。最后，与蛋白酶体相关的泛素链（K11和K48）作为突触前终末组装的信号。总的来说，我们提出了一种通过局部抑制UPS进行突触前组装的新的轴突内在机制。随后，处于多聚泛素化状态的蛋白质在局部积累触发了突触前膜的形成。
