2026年10月21日，美国华盛顿大学Jason J. Yi等科学家在《自然》发表研究，揭示了持续性神经元应激信号是安格曼综合征表型的基础。

安格曼综合征是一种严重的神经发育障碍，由UBE3A基因缺失引起，该基因编码一种E3泛素连接酶。安格曼综合征的机制尚不清楚，尤其是UBE3A底物与疾病表型之间的联系仍不确定。在此，研究人员利用UBE3A的功能获得性和功能缺失性突变，并结合无偏蛋白质组学，表明天冬酰胺合成酶（ASNS）是UBE3A的靶标。他们发现，在Ube3a缺失小鼠的大脑和人类神经元中，ASNS蛋白丰度增加。对ASNS过丰进行遗传校正可挽救小头畸形和许多行为缺陷。详细的分子分析表明，ASNS过丰激活应激信号，并导致神经元蛋白质合成整体减少。研究结果提示，UBE3A缺失使神经元陷入持续应激状态，并在发育敏感期阻碍神经元生长。此外，研究结果表明，靶向ASNS和应激反应可能在安格曼综合征中具有治疗潜力。

附：英文原文

Title: Persistent neuronal stress signalling underlies Angelman syndrome phenotypes

Author: Kim, Kwang-Soo, Gardner, Cory, Cullen, Alissa, Stelzer, Jalin A., Cho, Kevin, Sharma, Ashish, Nemera, Mati T., Law, Travis, Naz, Huma, Zhao, Guoyan, Gabel, Harrison W., Patti, Gary J., Musiek, Erik S., Ahn, Tae-Hyuk, Yi, Jason J.

Issue&Volume: 2026-10-21

Abstract: Angelman syndrome is a severe neurodevelopmental disorder caused by the loss of UBE3A, a gene that encodes an E3 ubiquitin ligase1,2. The mechanisms that underlie Angelman syndrome are not well understood, and in particular, the link between UBE3A substrates and disease phenotypes remains uncertain3. Here, using gain- and loss-of-function mutations in UBE3A4,5 along with unbiased proteomics, we show that asparagine synthetase (ASNS) is a target of UBE3A. We find that ASNS protein abundance is increased in the brains of Ube3a-null mice and in human neurons6. Genetic correction of ASNS overabundance rescues microcephaly and many behavioural deficits. Detailed molecular analyses show that ASNS overabundance activates stress signalling and causes a global reduction in neuronal protein synthesis. Our results suggest that loss of UBE3A traps neurons in a state of persistent stress and stunts neuronal growth during developmentally sensitive periods. Moreover, our results indicate that targeting ASNS and the stress response could hold therapeutic potential in Angelman syndrome.

DOI: 10.1038/s41586-026-11165-4

Source:https://www.nature.com/articles/s41586-026-11165-4