Abstract：
Neddylation is a cellular process in which the neural precursor cell expressed, developmentally down-regulated 8 (NEDD8) is conjugated to the lysine residue of target proteins via serial enzymatic cascades. Recently, it has been demonstrated that neddylation is required for synaptic clustering of metabotropic glutamate receptor 7 (mGlu7) and postsynaptic density protein 95 (PSD-95), and the inhibition of neddylation impairs neurite outgrowth and excitatory synaptic maturation. Similar to the balanced role of deubiquitylating enzymes (DUBs) in the ubiquitination process, we hypothesized that deneddylating enzymes can regulate neuronal development by counteracting the process of neddylation. We find that the SUMO peptidase family member, NEDD8 specific (SENP8) acts as a key neuronal deneddylase targeting the global neuronal substrates in primary rat cultured neurons. We demonstrate that SENP8 expression levels are developmentally regulated, peaking around the first postnatal week and gradually diminishing in mature brain and neurons. We find that SENP8 negatively regulates neurite outgrowth through multiple pathways, including actin dynamics, Wnt/β-catenin signaling, and autophagic processes. Alterations in neurite outgrowth by SENP8 subsequently result in the impairment of excitatory synapse maturation. Our data indicate that SENP8 plays an essential role in neuronal development and is a promising therapeutic target for neurodevelopmental disorders.
摘要：
Neddylation是神经前体细胞表达的细胞过程，发育下调的8（NEDD8）通过连续的酶级联与靶蛋白的赖氨酸残基缀合。最近,已经证明代谢型谷氨酸受体7（mGlu7）和突触后密度蛋白95（PSD-95）的突触聚集需要neddylation，neddylation的抑制会损害神经突的生长和兴奋性突触的成熟。类似于去泛素化酶（DUB）在泛素化过程中的平衡作用，我们假设deddylating酶可以通过抵消neddylation的过程来调节神经元的发育。我们发现SUMO肽酶家族成员，NEDD8特异性（SENP8）在原代大鼠培养的神经元中充当靶向全局神经元底物的关键神经元dendeddase。我们证明SENP8表达水平受发育调节，在出生后的第一周左右达到峰值，并在成熟的大脑和神经元中逐渐减少。我们发现SENP8通过多种途径负调节神经突生长，包括肌动蛋白动力学，Wnt/β-连环蛋白信号传导，和自噬过程。SENP8引起的神经突生长改变随后导致兴奋性突触成熟的损害。我们的数据表明SENP8在神经元发育中起着至关重要的作用，并且是神经发育障碍的有希望的治疗靶标。
