Excessive UBE3A dosage impairs retinoic acid signaling and synaptic plasticity in autism spectrum disorders

• 来源期刊: 细胞研究（英文版）
• 年，卷（期）: 2018,（1）
• 页码范围: 48-68
• 页数: 21页
• 语种: 英文
• DOI: 10.1038/cr.2017.132

摘要

The autism spectrum disorders (ASDs) are a collection of human neurological disorders with heterogeneous etiol ogies.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.