Over thirty years have passed since the first description of ubiquitin-positive structures in the brain of patients suffering from Alzheimer's disease. Meanwhile, the intracellular accumulation of ubiquitin-modified insoluble protein aggregates has become an indisputable hallmark of neurodegeneration. However, the role of ubiquitin and a fortiori the ubiquitin-proteasome system (UPS) in the pathogenesis of neurodevelopmental disorders (NDD) is much less described. In this article, we review all reported monogenic forms of NDD caused by lesions in genes coding for any component of the UPS including ubiquitin-activating (E1), -conjugating (E2) enzymes, ubiquitin ligases (E3), ubiquitin hydrolases, and ubiquitin-like modifiers as well as proteasome subunits. Strikingly, our analysis revealed that a vast majority of these proteins have a described function in the negative regulation of the innate immune response. In this work, we hypothesize a possible involvement of autoinflammation in NDD pathogenesis. Herein, we discuss the parallels between immune dysregulation and neurodevelopment with the aim at improving our understanding the biology of NDD and providing knowledge required for the design of novel therapeutic strategies.

中文翻译：

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泛素-蛋白酶体系统 (UPS) 基因组改变引起的神经发育障碍 (NDD)：免疫失调对疾病发病机制的可能贡献。

自从首次描述阿尔茨海默病患者大脑中的泛素阳性结构以来，已经过去了三十多年。同时，泛素修饰的不溶性蛋白质聚集体的细胞内积累已成为神经退行性疾病无可争议的标志。然而，泛素和更重要的泛素-蛋白酶体系统 (UPS) 在神经发育障碍 (NDD) 发病机制中的作用鲜为人知。在本文中，我们回顾了所有报道的由编码 UPS 任何成分的基因损伤引起的 NDD 单基因形式，包括泛素激活 (E1)、-结合 (E2) 酶、泛素连接酶 (E3)、泛素水解酶和泛素-样修饰符以及蛋白酶体亚基。引人注目的是，我们的分析表明，绝大多数这些蛋白质在先天免疫反应的负调节中具有所描述的功能。在这项工作中，我们假设自身炎症可能参与 NDD 发病机制。在此，我们讨论了免疫失调和神经发育之间的相似之处，旨在提高我们对 NDD 生物学的理解，并提供设计新治疗策略所需的知识。