Abstract
Angelman syndrome (AS) is a neurodevelopmental disorder that results from deletions or mutations in chromosome 15, which usually includes the UBE3A gene. Ube3A protein is an E3 ubiquitin ligase that ubiquitinates proteins and targets them for degradation. The immediate-early gene Arc, a master regulator of synaptic plasticity, was identified as a putative substrate of Ube3A, but there have been conflicting reports on whether Arc is a bona fide E3 ligase substrate. Using multiple approaches, we found no evidence for a physical interaction between Arc and Ube3A in vivo. Nonetheless, activity-induced subcellular distribution of Arc is altered in brains from Ube3am−/p+ mice, with abnormal concentration of Arc at synapses. Furthermore, although activation of Arc transcription is normal, the stability of Arc protein is enhanced in dendrites of hippocampal neurons cultured from Ube3am−/p+ mice. Finally, homeostatic synaptic scaling of surface AMPA receptors does not occur in Ube3am−/p+ hippocampal neurons, reminiscent of neurons that lack Arc protein. Although Ube3A does not seem to bind Arc in a canonical E3 ligase-substrate interaction, Arc-dependent synaptic plasticity is still altered in Ube3am−/p+ mice, which may underlie the cognitive deficits observed in AS.
Highlights
Angelman syndrome (AS) is a neurodevelopmental disorder affecting about one in 15,000 children, and presents with intellectual disability, ataxia, inability to acquire language and seizures (Clayton-Smith and Laan, 2003; Dagli et al, 2011)
In order to determine whether Arc and Ube3A interact in vivo (Figure 1), we conducted coimmunoprecipitation experiments from brain tissue
When all experiments are combined, we did not observe a significant difference in basal Arc expression between genotypes due variability across cultures. This is most likely explained by variability in activity levels across cultures. These results suggest that Arc is initially induced normally in Ube3am−/p+ neurons, but that increased stability of Arc protein may result in accumulation of Arc in dendrites after induction
Summary
Angelman syndrome (AS) is a neurodevelopmental disorder affecting about one in 15,000 children, and presents with intellectual disability, ataxia, inability to acquire language and seizures (Clayton-Smith and Laan, 2003; Dagli et al, 2011). AS is caused by deletions or copy number variants in the region containing the maternally-inherited allele of the gene UBE3A on the 15q11.2-13 chromosome (Williams et al, 2006). This gene encodes the E3 ubiquitin ligase Ube3A (Kishino et al, 1997; Matsuura et al, 1997), which is imprinted in most parts of the brain (Albrecht et al, 1997; Rougeulle et al, 1997). A mouse model of AS, Ube3am−/p+, has a deletion of the maternal allele of the UBE3A gene, while the paternal allele is still present and is epigenetically silenced in most brain regions (Jiang et al, 1998). AS mice recapitulate many of the same features as humans with AS, including gait and balance problems, deficits in context-dependent learning and seizures (Jiang et al, 1998; Miura et al, 2002; Yashiro et al, 2009)
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