Interested in what research has been published about AS?

Dr. Ed Weeber will tell us how we can search for information and some of the latest research happening around the globe.

 How can you get published scientific articles concerning Angelman syndrome research? By accessing the free data base called PubMed (www.pubmed.gov). This valuable resource is developed and maintained by the National Center for Biotechnology Information (NCBI) at the National Library of Medicine (NLM) and contains more than 20 million references to scientific articles. The search function allows single or multiple terms to narrow the number of “hits”. In addition, you can search for authors in order to find all of the publications from a specific researcher.   Many of these publications are free and all of them have an abstract to describe the research.

A search for the term “Angelman syndrome” will reveal 1300 publications with the earliest dating back to 1950. To make the science a little easier to digest, every issue will present a selection of the latest published scientific articles with Angelman syndrome in the title, abstract or key words section of the paper.  Below are some recent papers that have come out in the last few months.

Title: Recurrent fractures as a new skeletal problem in the course of Angelman syndrome.

Journal: Bone

Authors: Rusińska A, Dzwonek AB, Chlebna-Sokół D.

Department of Pediatric Propedeutics and Metabolic Bone Diseases, Medical University of Lodz, Poland; Maria Konopnicka Memorial Teaching Hospital No. 4, Medical University of Lodz, Poland.

Abstract:

Angelman syndrome is a genetically inherited syndrome with severe retardation of psychomotor development and speech disturbances, usually accompanied by epilepsy, typical dysmorphic features, and some skeletal symptoms. The aim of the current report is to present new skeletal symptoms which may occur in the course of AS, based on a case report of an 8-year-old girl with confirmed 15q11;12 microdeletion and recurrent low-trauma bone fractures. According to our knowledge it is the first report of such skeletal symptoms in patient with a diagnosis of AS.

Title: Role of the ubiquitin ligase E6AP/UBE3A in controlling levels of the synaptic protein Arc.

Journal: Proc Natl Acad Sci U S A

Authors: Kühnle S, Mothes B, Matentzoglu K, Scheffner M.

Department of Biology and Konstanz Research School Chemical Biology, University of Konstanz, 78457 Konstanz, Germany.

Abstract:

Inactivation of the ubiquitin ligase E6 associated protein (E6AP) encoded by the UBE3A gene has been associated with development of the Angelman syndrome. Recently, it was reported that in mice, loss of E6AP expression results in increased levels of the synaptic protein Arc and a concomitant impaired synaptic function, providing an explanation for some phenotypic features of Angelman syndrome patients. Accordingly, E6AP has been shown to negatively regulate activity-regulated cytoskeleton-associated protein (Arc) and it has been suggested that E6AP targets Arc for ubiquitination and degradation. In our study, we provide evidence that Arc is not a direct substrate for E6AP and binds only weakly to E6AP, if at all. Furthermore, we show that down-regulation of E6AP expression stimulates estradiol-induced transcription of the Arc gene. Thus, we propose that Arc protein levels are controlled by E6AP at the transcriptional rather than at the posttranslational level.

Title: Proteomic profiling in Drosophila reveals potential Dube3a regulation of the actin cytoskeleton and neuronal homeostasis.

Journal: PLoS One

Authors: Jensen L, Farook MF, Reiter LT.

Department of Neurology, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America.

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.