Abstract
This report is a meeting summary of the 2010 Angelman Syndrome Foundation's scientific symposium on the neuroscience of UBE3A. Angelman syndrome is characterized by loss of speech, severe developmental delay, seizures, and ataxia. These core symptoms are caused by maternal allele disruptions of a single gene—UBE3A. UBE3A encodes an E3 ubiquitin ligase that targets certain proteins for proteasomal degradation. This biology has led to the expectation that the identification of Ube3a protein targets will lead to therapies for Angelman syndrome. The recent discovery of Ube3a substrates such as Arc (activity-regulated cytoskeletal protein) provides new insight into the mechanisms underlying the synaptic function and plasticity deficits caused by the loss of Ube3a. In addition to identifying Ube3a substrates, there have also been recent advances in understanding UBE3A's integrated role in the neuronal repertoire of genes and protein interactions. A developmental picture is now emerging whereby UBE3A gene dosage on chromosome 15 alters synaptic function, with deficiencies leading to Angelman syndrome and overexpression associated with classic autism symptomatology.
Highlights
The 2010 scientific symposium was held June 15–16 in Chapel Hill, NC
What might underlie the synaptic and plasticity deficits observed in Ube3a-deficient mice? many factors are likely to contribute, the increases in Arc expression observed in Ube3a-deficient mice could explain both the loss of functional synapses, due to the loss of AMPA receptor (AMPAR), and deficits in synaptic plasticity, due to aberrant AMPAR trafficking
We are gaining a better understanding of the biological actions of UBE3A as more neuroscientists investigate its role in neural plasticity and learning
Summary
The 2010 scientific symposium was held June 15–16 in Chapel Hill, NC. The symposium is conducted annually by the Angelman Treatment and Research Institute, a part of the Angelman Syndrome Foundation (www.angelman.org). Many factors are likely to contribute, the increases in Arc expression observed in Ube3a-deficient mice (noted above) could explain both the loss of functional synapses, due to the loss of AMPARs, and deficits in synaptic plasticity, due to aberrant AMPAR trafficking. Ultrasonic vocalization recordings in newborns revealed that maternal deletion pups emitted significantly more vocalizations than wild-type littermates, but the behavioral correlate to communication deficits observed in human AS is unclear This mouse model will be invaluable to future AS research and will help to provide a biological basis for the more severe deficits in speech and epilepsy observed in AS individuals with 15q11–q13 deletions compared to those with Ube3a mutations (Lossie et al 2001). While gene therapy may not present a readily viable option for restoring Ube3a levels in the brain and treating AS, the expectation is that advances in gene therapy may someday make this approach viable
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