Bi Xiaoning, Sun Jiandong, Ji Angela X, Baudry Michel
a Department of Basic Medical Sciences, COMP , Western University of Health Sciences , Pomona , CA , USA.
b Graduate College of Biomedical Sciences , Western University of Health Sciences , Pomona , CA , USA.
Expert Opin Ther Targets. 2016;20(5):601-13. doi: 10.1517/14728222.2016.1115837. Epub 2015 Nov 26.
Angelman syndrome (AS) is a neurodevelopmental disorder caused by deficiency of maternally inherited UBE3A, an ubiquitin E3 ligase. Despite recent progress in understanding the mechanism underlying UBE3A imprinting, there is no effective treatment. Further investigation of the roles played by UBE3A in the central nervous system (CNS) is needed for developing effective therapies.
This review covers the literature related to genetic classifications of AS, recent discoveries regarding the regulation of UBE3A imprinting, alterations in cell signaling in various brain regions and potential therapeutic approaches. Since a large proportion of AS patients exhibit comorbid autism spectrum disorder (ASD), potential common molecular bases are discussed.
Advances in understanding UBE3A imprinting provide a unique opportunity to induce paternal UBE3A expression, thus targeting the syndrome at its 'root.' However, such efforts have yielded less-than-expected rescue effects in AS mouse models, raising the concern that activation of paternal UBE3A after a critical period cannot correct all the CNS defects that developed in a UBE3A-deficient environment. On the other hand, targeting abnormal downstream cell signaling pathways has provided promising rescue effects in preclinical research. Thus, combined reinstatement of paternal UBE3A expression with targeting abnormal signaling pathways should provide better therapeutic effects.
天使综合征（AS）是一种神经发育障碍，由母系遗传的泛素E3连接酶UBE3A缺乏所致。尽管在理解UBE3A印记背后的机制方面取得了最新进展，但仍没有有效的治疗方法。为了开发有效的治疗方法，需要进一步研究UBE3A在中枢神经系统（CNS）中的作用。
本综述涵盖了与AS的基因分类、关于UBE3A印记调控的最新发现、不同脑区细胞信号传导的改变以及潜在治疗方法相关的文献。由于很大一部分AS患者表现出共患自闭症谱系障碍（ASD），因此讨论了潜在的共同分子基础。
在理解UBE3A印记方面的进展提供了一个独特的机会来诱导父源UBE3A表达，从而从根源上针对该综合征。然而，这些努力在AS小鼠模型中产生的挽救效果低于预期，这引发了人们的担忧，即在关键期后激活父源UBE3A无法纠正在UBE3A缺陷环境中发展出的所有CNS缺陷。另一方面，针对异常的下游细胞信号通路在临床前研究中提供了有希望的挽救效果。因此，恢复父源UBE3A表达与靶向异常信号通路相结合应能提供更好的治疗效果。
