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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