Excessive UBE3A dosage impairs retinoic acid signaling and synaptic plasticity in autism spectrum disorders
Excessive UBE3A dosage impairs retinoic acid signaling and synaptic plasticity in autism spectrum disorders
复制标题
过量的 UBE3A 剂量会损害自闭症谱系障碍中的视黄酸信号传导和突触可塑性。
DOI：
10.1038/cr.2017.132
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发表时间：
2018-01-01
期刊：
影响因子：
44.1
通讯作者：
Hu, Ronggui
中科院分区：
文献类型：
--
作者：
Xu, Xingxing;Li, Chuanyin;Hu, Ronggui
自闭症谱系障碍（ASDs）是一种具有异质病因的人类神经系统疾病的集合。E3泛素（Ub）连接酶UBE3A的过度活跃，源于15q11-q13拷贝数的变化，占全球ASD病例的1%-3%，但其潜在机制尚未完全确定。在这里，我们报道了ALDH1A2的功能，视黄酸（RA）合成的限速酶，由UBE3A以泛素化依赖的方式负调控。过量的UBE3A剂量会损害ra介导的神经元稳态突触可塑性。通过在小鼠前额皮质过度表达UBE3A或给药ALDH1A拮抗剂，重现asd样症状，而RA补充剂可显著减轻过量UBE3A剂量诱导的asd样表型。通过确定RA信号减少是与UBE3A过度活跃相关的ASD表型的潜在机制，我们的研究结果为ASD病因学提供了新的视角，并促进了针对这种日益流行的疾病的治疗开发模式。
The autism spectrum disorders (ASDs) are a collection of human neurological disorders with heterogeneous etiologies. Hyperactivity of E3 ubiquitin (Ub) ligase UBE3A, stemming from 15q11-q13 copy number variations, accounts for 1%-3% of ASD cases worldwide, but the underlying mechanisms remain incompletely characterized. Here we report that the functionality of ALDH1A2, the rate-limiting enzyme of retinoic acid (RA) synthesis, is negatively regulated by UBE3A in a ubiquitylation-dependent manner. Excessive UBE3A dosage was found to impair RA-mediated neuronal homeostatic synaptic plasticity. ASD-like symptoms were recapitulated in mice by overexpressing UBE3A in the prefrontal cortex or by administration of an ALDH1A antagonist, whereas RA supplements significantly alleviated excessive UBE3A dosage-induced ASD-like phenotypes. By identifying reduced RA signaling as an underlying mechanism in ASD phenotypes linked to UBE3A hyperactivities, our findings introduce a new vista of ASD etiology and facilitate a mode of therapeutic development against this increasingly prevalent disease.