Department of Medicine, Division of Endocrinology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands.
Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.
Int J Mol Sci. 2022 Dec 24;24(1):303. doi: 10.3390/ijms24010303.
Angelman Syndrome (AS) is a severe neurodevelopmental disorder, caused by the neuronal absence of the ubiquitin protein ligase E3A (UBE3A). UBE3A promotes ubiquitin-mediated protein degradation and functions as a transcriptional coregulator of nuclear hormone receptors, including the glucocorticoid receptor (GR). Previous studies showed anxiety-like behavior and hippocampal-dependent memory disturbances in AS mouse models. Hippocampal GR is an important regulator of the stress response and memory formation, and we therefore investigated whether the absence of UBE3A in AS mice disrupted GR signaling in the hippocampus. We first established a strong cortisol-dependent interaction between the GR ligand binding domain and a UBE3A nuclear receptor box in a high-throughput interaction screen. In vivo, we found that UBE3A-deficient AS mice displayed significantly more variation in circulating corticosterone levels throughout the day compared to wildtypes (WT), with low to undetectable levels of corticosterone at the trough of the circadian cycle. Additionally, we observed an enhanced transcriptomic response in the AS hippocampus following acute corticosterone treatment. Surprisingly, chronic corticosterone treatment showed less contrast between AS and WT mice in the hippocampus and liver transcriptomic responses. This suggests that UBE3A limits the acute stimulation of GR signaling, likely as a member of the GR transcriptional complex. Altogether, these data indicate that AS mice are more sensitive to acute glucocorticoid exposure in the brain compared to WT mice. This suggests that stress responsiveness is altered in AS which could lead to anxiety symptoms.
天使综合征（AS）是一种严重的神经发育障碍，由泛素蛋白连接酶 E3A（UBE3A）的神经元缺失引起。UBE3A 促进泛素介导的蛋白质降解，并作为核激素受体（包括糖皮质激素受体（GR））的转录共调节剂发挥作用。先前的研究表明，AS 小鼠模型存在焦虑样行为和海马依赖性记忆障碍。海马 GR 是应激反应和记忆形成的重要调节剂，因此我们研究了 AS 小鼠中 UBE3A 的缺失是否会破坏海马中的 GR 信号传导。我们首先在高通量相互作用筛选中建立了 GR 配体结合域与 UBE3A 核受体盒之间的强皮质酮依赖性相互作用。在体内，我们发现与野生型（WT）相比，UBE3A 缺陷型 AS 小鼠全天的循环皮质酮水平变化明显更大，在昼夜节律的低谷处皮质酮水平低至无法检测。此外，我们观察到急性皮质酮处理后 AS 海马中的转录组反应增强。令人惊讶的是，慢性皮质酮处理后，AS 和 WT 小鼠海马和肝脏转录组反应之间的差异较小。这表明 UBE3A 限制了 GR 信号的急性刺激，可能作为 GR 转录复合物的成员。总的来说，这些数据表明与 WT 小鼠相比，AS 小鼠对大脑中急性糖皮质激素暴露更敏感。这表明 AS 中的应激反应发生改变，可能导致焦虑症状。
