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Excessive UBE3A dosage impairs retinoic acid signaling and synaptic plasticity in autism spectrum disorders
- Publication Year :
- 2017
- Publisher :
- Nature Publishing Group, 2017.
-
Abstract
- 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.
- Subjects :
- 0301 basic medicine
Male
congenital, hereditary, and neonatal diseases and abnormalities
Autism Spectrum Disorder
Ubiquitin-Protein Ligases
Retinoic acid
Tretinoin
Biology
Aldehyde Dehydrogenase 1 Family
ALDH1A2
03 medical and health sciences
chemistry.chemical_compound
Ubiquitin
Neuroplasticity
mental disorders
UBE3A
medicine
Animals
Humans
Molecular Targeted Therapy
Prefrontal cortex
Molecular Biology
Neurons
Neuronal Plasticity
Ubiquitination
Retinal Dehydrogenase
Cell Biology
medicine.disease
Mice, Inbred C57BL
030104 developmental biology
HEK293 Cells
chemistry
Child, Preschool
Synaptic plasticity
biology.protein
Autism
Original Article
Neuroscience
Signal Transduction
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....07ecbccb6a5af8291ae593ad505fe1c7