In chromosomal structure analyses, we found four de novo CNVs and one de novo chromosomal rearrangement event, including a de novo duplication of UBE3A-containing region at 15q11.2-q13.1, which causes Angelman syndrome and microcephaly, and a disrupted TNR due to de novo chromosomal translocation t(1; 5)(q25.1; q33.2).
Given the role of mPFC in neurodevelopmental disorders including autism, we aimed to identify the functional changes resulting from loss of UBE3A in infralimbic and prelimbic mPFC areas in a mouse model of AS.
Up till now, all the published studies have examined the role of the ubiquitin-protein ligase activity of E6AP in the development of AS, and it is not known what role the newly discovered coactivation functions of E6AP and ER plays in the pathology of AS.
This work indicates a feedback mechanism in the interplay between PKA and E6ap, which may prove crucial for the role of both proteins in cancers and neurogenetic diseases like Angelman syndrome.
Quantitative proteomics reveals neuronal ubiquitination of Rngo/Ddi1 and several proteasomal subunits by Ube3a, accounting for the complexity of Angelman syndrome.
Ube3a ubiquinates p18, resulting in its proteasomal degradation, and Ube3a deficiency in the hippocampus of AS mice induces increased lysosomal localization of p18 and other members of the Ragulator-Rag complex, and increased mTORC1 activity. p18 knockdown in hippocampal CA1 neurons of AS mice reduces elevated mTORC1 activity and improves dendritic spine maturation, long-term potentiation (LTP), as well as learning performance.
Here we use touchscreen visual discrimination learning to evaluate performance in the maternally derived Ube3a mouse model of Angelman syndrome, the Ts65Dn trisomy mouse model of Down syndrome, and the Mecp2<sup>Bird</sup> mouse model of Rett syndrome.
Angelman syndrome (AS) is a neurodevelopmental disorder caused by deletion of the maternally inherited 15q11q13 region, paternal uniparental disomy 15 [upd(15)pat], an imprinting defect of the maternal chromosome region 15q11q13, or a pathogenic mutation of the maternal UBE3A allele.
Angelman syndrome (AS) is a neurogenetic imprinting disorder caused by loss of the maternally inherited Ube3a gene and is characterized by generalized epilepsy, limited expressive speech, sleep dysfunction, and movement disorders.
These results indicate sociability is repressed by social experience and the endogenous levels of UBE3A protein and suggest some social behavioral features observed in Angelman syndrome may reflect an increased social motivation.
Here, we report that ganaxolone, a synthetic neurosteroid that acts as a positive allosteric modulator of synaptic and extrasynaptic GABA<sub>A</sub> receptors, was anxiolytic, anticonvulsant, and improved motor deficits in the Ube3a-deficient mouse model of AS when administered by implanted mini-pump for 3 days or 4 weeks.
Interestingly, HDAC inhibitor also significantly increased the expression of Ube3a in cultured neuronal cells and in the brain of wild type mice but not in AS mice.
UBE3A-maternal deficient mice (AS mice) exhibit many typical features of AS including cognitive and motor deficits but the underlying mechanism of these behavioral abnormalities is poorly understood.
Although Ube3A does not seem to bind Arc in a canonical E3 ligase-substrate interaction, Arc-dependent synaptic plasticity is still altered in <i>Ube3a</i><sup><i>m</i>-/<i>p</i>+</sup> mice, which may underlie the cognitive deficits observed in AS.
Angelman syndrome (AS) is a neurogenetic disorder caused by deletion of the maternally inherited UBE3A allele and is characterized by developmental delay, intellectual disability, ataxia, seizures and a happy affect.
We have shown that neuronal activity shifts the balance toward stabilization of Rnf2 through self-polyubiquitination rather than triggering its degradation through polyubiquitination by Ube3A, an E3 ligase implicated in Angelman Syndrome.
The UBE3A gene demonstrates maternal-specific expression in neurons and loss of maternal UBE3A causes Angelman syndrome, a neurodevelopmental disorder with some overlapping neurological features to Dup15q.
Testing for UBE3A intragenic exonic deletions should be performed in those AS patients with a normal methylation pattern and no mutations in the UBE3A gene.