Abstract: The molecular defects associated with Angelman syndrome( AS) and 15q duplication autism are directly correlated to expression levels of the E3 ubiquitin ligase protein UBE3A. Here we used Drosophila melanogaster to screen for the targets of this ubiquitin ligase under conditions of both decreased( as in AS) or increased( as in dup( 15)) levels of the fly Dube3a or human UBE3A proteins. Using liquid phase isoelectric focusing of proteins from whole fly head extracts we identified a total of 50 proteins that show changes in protein, and in some cases transcriptional levels, when Dube3a fluctuates. We analyzed head extracts from cytoplasmic, nuclear and membrane fractions for Dube3a regulated proteins. Our results indicate that Dube3a is involved in the regulation of cellular functions related to ATP synthesis / metabolism, actin cytoskeletal integrity, both catabolism and carbohydrate metabolism as well as nervous system development and function. Sixty-two percent of the proteins were > 50 % identical to homologous human proteins and 8 have previously be shown to be ubiquitinated in the fly nervous system. Eight proteins may be regulated by Dube3a at the transcript level through the transcriptional co-activation function of Dube3a. We investigated one autism-associated protein, ATPα, and found that it can be ubiquitinated in a Dube3a dependent manner. We also found that Dube3a mutants have significantly less filamentous actin than wild type larvae consistent with the identification of actin targets regulated by Dube3a. The identification of UBE3A targets is the first step in unraveling the molecular etiology of AS and duplication 15q autism.
Title: Discrimination training reduces high rate social approach behaviors in Angelman syndrome: proof of principle. Journal: Res Dev Disabil. Authors: Heald M, Allen D, Villa D, Oliver C. Cerebra Centre for Neurodevelopmental Disorders, School of Psychology, University of Birmingham, Edgbaston B15 2TT, UK. mxo988 @ bham. ac. uk
Abstract: This proof of principle study was designed to evaluate whether excessively high rates of social approach behaviors in children with Angelman syndrome( AS) can be modified using a multiple schedule design. Four children with AS were exposed to a multiple schedule arrangement, in which social reinforcement and extinction, cued using a novel stimulus, were alternated. Twenty-five to 35 discrimination training sessions were conducted and levels of approach behaviors were measured before and after the discrimination training for two children. All four participants evidenced discrimination between conditions of reinforcement and extinction after 16-20 teaching sessions as indicated by lower rates of social approach behaviors in the presence of the S( Δ) for extinction. Reversal effects for the two children for whom this design was implemented were evident. The results demonstrate that after repeated training, the use of a novel stimulus can serve as a cue for children with AS to discriminate adult availability. This is a potentially effective component of a broader intervention strategy but highlights the need for sustained teaching procedures within this population.
Title: The Angelman syndrome protein Ube3a / E6AP is required for Golgi acidification and surface protein sialylation. Journal: J Neurosci. Authors: Condon KH, Ho J, Robinson CG, Hanus C, Ehlers MD. Department of Neurobiology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Abstract: Angelman syndrome( AS) is a severe disorder of postnatal brain development caused by neuron-specific loss of the HECT( homologous to E6AP carboxy terminus) domain E3 ubiquitin ligase Ube3a / E6AP. The cellular role of Ube3a remains enigmatic despite recent descriptions of synaptic and behavioral deficits in AS mouse models. Although neuron-specific imprinting is thought to limit the disease to the brain, Ube3a is expressed ubiquitously, suggesting a broader role in cellular function. In the current study, we demonstrate a profound structural disruption and cisternal swelling of the Golgi apparatus( GA) in the cortex of AS( UBE3A( m- / p +)) mice. In Ube3a knockdown cell lines and UBE3A( m- / p +) cortical neurons, the GA is severely under-acidified, leading to osmotic swelling. Both in vitro and in vivo, the loss of Ube3a and corresponding elevated pH of the GA is associated with a marked reduction in protein sialylation, a process highly dependent on intralumenal Golgi pH. Altered ion homeostasis of the GA may provide a common cellular pathophysiology underlying the diverse plasticity and neurodevelopmental deficits associated with AS.
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