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Excessive UBE3A dosage impairs retinoic acid signaling and synaptic plasticity in autism spectrum disorders
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Excessive UBE3A dosage impairs retinoic acid signaling and synaptic plasticity in autism spectrum disorders
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Journal Article
Excessive UBE3A dosage impairs retinoic acid signaling and synaptic plasticity in autism spectrum disorders
2018
Overview
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 15qll-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 reg- ulated 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 alle- viated 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.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ Animals
/ Autism
/ Autism Spectrum Disorder - drug therapy
/ Autism Spectrum Disorder - metabolism
/ Biomedical and Life Sciences
/ Dosage
/ Etiology
/ Humans
/ Male
/ Original
/ Retinal Dehydrogenase - metabolism
/ Rodents
/ Ubiquitin-Protein Ligases - genetics
