Filonova Irina, Trotter Justin H, Banko Jessica L, Weeber Edwin J
Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Byrd Alzheimer's Institute, Tampa, Florida 33613, USA.
Learn Mem. 2014 Jan 16;21(2):98-104. doi: 10.1101/lm.032375.113.
Angelman Syndrome (AS) is a devastating neurological disorder caused by disruption of the maternal UBE3A gene. Ube3a protein is identified as an E3 ubiquitin ligase that shows neuron-specific imprinting. Despite extensive research evaluating the localization and basal expression profiles of Ube3a in mouse models, the molecular mechanisms whereby Ube3a deficiency results in AS are enigmatic. Using in vitro and in vivo systems we show dramatic changes in the expression of Ube3a following synaptic activation. In primary neuronal culture, neuronal depolarization was found to increase both nuclear and cytoplasmic Ube3a levels. Analogous up-regulation in maternal and paternal Ube3a expression was observed in Ube3a-YFP reporter mice following fear conditioning. Absence of Ube3a led to deficits in the activity-dependent increases in ERK1/2 phosphorylation, which may contribute to reported deficits in synaptic plasticity and cognitive function in AS mice. Taken together, our findings provide novel insight into the regulation of Ube3a by synaptic activity and its potential role in kinase regulation.
天使综合征（Angelman Syndrome，AS）是一种由母源UBE3A基因功能缺失引起的严重神经发育障碍性疾病。Ube3a蛋白被鉴定为一种具有神经元特异性印记的E3泛素连接酶。尽管针对Ube3a在小鼠模型中的定位和基础表达谱进行了广泛研究，但Ube3a缺乏导致AS的分子机制仍不清楚。我们利用体外和体内系统发现，突触激活后Ube3a的表达发生了显著变化。在原代神经元培养中，发现神经元去极化会增加细胞核和细胞质中Ube3a的水平。在恐惧条件反射后，Ube3a-YFP报告基因小鼠的母源和父源Ube3a表达也出现了类似的上调。Ube3a的缺失导致ERK1/2磷酸化的活性依赖性增加出现缺陷，这可能是AS小鼠突触可塑性和认知功能缺陷的原因。综上所述，我们的研究结果为突触活动对Ube3a的调控及其在激酶调节中的潜在作用提供了新的见解。
