背景:认知障碍是唐氏综合症(DS)的核心特征,和潜在的神经生物学机制仍不清楚。翻译失调与以认知障碍为特征的多种神经系统疾病有关。翻译因子真核延伸因子2(eEF2)通过其激酶eEF2K的磷酸化导致一般蛋白质合成的抑制。
方法:我们使用遗传和药理学方法在两系DS小鼠模型中抑制eEF2K。我们进一步应用多种方法来评估eEF2K抑制对DS病理生理学的影响。
结果:我们发现DS和DS小鼠模型患者的大脑中eEF2K信号传导过度活跃。通过抑制DS模型小鼠的eEF2K来抑制eEF2磷酸化改善了DS相关病理生理学的多个方面,包括从头蛋白合成缺陷,突触形态缺陷,长期突触可塑性衰竭,和认知障碍。
结论:我们的数据表明eEF2K信号传导失调介导DS相关的突触和认知障碍。
结论:唐氏综合征(DS)脑中翻译因子真核延伸因子2(eEF2)的磷酸化增加。eEF2激酶(eEF2K)的抑制减轻DS模型中的认知缺陷。抑制eEF2K改善DS模型中的突触失调。DS模型中的认知和突触损伤由eEF2K抑制剂挽救。
BACKGROUND: Cognitive impairment is a core feature of Down syndrome (DS), and the underlying neurobiological mechanisms remain unclear. Translation dysregulation is linked to multiple neurological disorders characterized by cognitive impairments. Phosphorylation of the translational factor eukaryotic elongation factor 2 (eEF2) by its kinase eEF2K results in inhibition of general protein synthesis.
METHODS: We used genetic and pharmacological methods to suppress eEF2K in two lines of DS mouse models. We further applied multiple approaches to evaluate the effects of eEF2K inhibition on DS pathophysiology.
RESULTS: We found that eEF2K signaling was overactive in the brain of patients with DS and DS mouse models. Inhibition of eEF2 phosphorylation through suppression of eEF2K in DS model mice improved multiple aspects of DS-associated pathophysiology including de novo protein synthesis deficiency, synaptic morphological defects, long-term synaptic plasticity failure, and cognitive impairments.
CONCLUSIONS: Our data suggested that eEF2K signaling dysregulation mediates DS-associated synaptic and cognitive impairments.
CONCLUSIONS: Phosphorylation of the translational factor eukaryotic elongation factor 2 (eEF2) is increased in the Down syndrome (DS) brain. Suppression of the eEF2 kinase (eEF2K) alleviates cognitive deficits in DS models. Suppression of eEF2K improves synaptic dysregulation in DS models. Cognitive and synaptic impairments in DS models are rescued by eEF2K inhibitors.