Department of Fundamental Neurosciences, University of Lausanne, Lausanne, Switzerland; Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy.
Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, New York City, NY, USA.
Neuron. 2019 Mar 20;101(6):1070-1088. doi: 10.1016/j.neuron.2019.02.041.
Altered synaptic structure and function is a major hallmark of fragile X syndrome (FXS), autism spectrum disorders (ASDs), and other intellectual disabilities (IDs), which are therefore classified as synaptopathies. FXS and ASDs, while clinically and genetically distinct, share significant comorbidity, suggesting that there may be a common molecular and/or cellular basis, presumably at the synapse. In this article, we review brain architecture and synaptic pathways that are dysregulated in FXS and ASDs, including spine architecture, signaling in synaptic plasticity, local protein synthesis, (m)RNA modifications, and degradation. mRNA repression is a powerful mechanism for the regulation of synaptic structure and efficacy. We infer that there is no single pathway that explains most of the etiology and discuss new findings and the implications for future work directed at improving our understanding of the pathogenesis of FXS and related ASDs and the design of therapeutic strategies to ameliorate these disorders.
突触结构和功能的改变是脆性 X 综合征 (FXS)、自闭症谱系障碍 (ASD) 和其他智力障碍 (ID) 的主要标志，因此这些疾病被归类为突触病。FXS 和 ASD 在临床上和遗传上是不同的，但它们有显著的共病性，这表明可能存在共同的分子和/或细胞基础，大概在突触上。在本文中，我们综述了 FXS 和 ASD 中失调的大脑结构和突触通路，包括脊柱结构、突触可塑性中的信号转导、局部蛋白质合成、(m)RNA 修饰和降解。mRNA 抑制是调节突触结构和功能的一种强大机制。我们推断，没有一个单一的途径可以解释大多数病因，并讨论新的发现及其对未来工作的意义，这些工作旨在提高我们对 FXS 和相关 ASD 发病机制的理解，并设计改善这些疾病的治疗策略。
