Trobiani Laura, Meringolo Maria, Diamanti Tamara, Bourne Yves, Marchot Pascale, Martella Giuseppina, Dini Luciana, Pisani Antonio, De Jaco Antonella, Bonsi Paola
Dept. Biology and Biotechnology, Sapienza University of Rome, P.le Aldo Moro 5, 00185 Rome, Italy.
Lab. Neurophysiology and Plasticity, IRCCS Fondazione Santa Lucia, Via del Fosso di Fiorano 64, 00143 Rome, Italy; Dept. Systems Medicine, University Tor Vergata, Via Montpellier 1, 00133 Rome, Italy.
Neurosci Biobehav Rev. 2020 Dec;119:37-51. doi: 10.1016/j.neubiorev.2020.09.017. Epub 2020 Sep 28.
The genetics underlying autism spectrum disorder (ASD) is complex and heterogeneous, and de novo variants are found in genes converging in functional biological processes. Neuronal communication, including trans-synaptic signaling involving two families of cell-adhesion proteins, the presynaptic neurexins and the postsynaptic neuroligins, is one of the most recurrently affected pathways in ASD. Given the role of these proteins in determining synaptic function, abnormal synaptic plasticity and failure to establish proper synaptic contacts might represent mechanisms underlying risk of ASD. More than 30 mutations have been found in the neuroligin genes. Most of the resulting residue substitutions map in the extracellular, cholinesterase-like domain of the protein, and impair protein folding and trafficking. Conversely, the stalk and intracellular domains are less affected. Accordingly, several genetic animal models of ASD have been generated, showing behavioral and synaptic alterations. The aim of this review is to discuss the current knowledge on ASD-linked mutations in the neuroligin proteins and their effect on synaptic function, in various brain areas and circuits.
自闭症谱系障碍（ASD）背后的遗传学复杂且具有异质性，在功能生物学过程中汇聚的基因中发现了新生变异。神经元通讯，包括涉及两类细胞粘附蛋白（突触前神经连接蛋白和突触后神经配蛋白）的跨突触信号传导，是ASD中最常受影响的途径之一。鉴于这些蛋白在决定突触功能中的作用，异常的突触可塑性和无法建立适当的突触联系可能是ASD风险的潜在机制。在神经配蛋白基因中已发现30多种突变。大多数产生的氨基酸替代位于该蛋白的细胞外胆碱酯酶样结构域，损害蛋白质折叠和运输。相反，柄部和细胞内结构域受影响较小。因此，已经产生了几种ASD的遗传动物模型，显示出行为和突触改变。本综述的目的是讨论目前关于神经配蛋白中与ASD相关的突变及其对不同脑区和神经回路中突触功能影响的知识。
