G·A·B·B·A

Angelman Syndrome (AS) is a neurobehavioral disorder, characterized by severe mental retardation, motor dysfunction, absence of speech, autism and epilepsy. The loss of a functional copy of the maternal UBE3A gene is primarily responsible for causing the disease, since the paternal copy of this gene is imprinted in the brain.
The UBE3A gene encodes the ubiquitin protein ligase E6AP, which is a member of the E3A family of ubiquitin protein ligases, and is involved in proteosome mediated degradation of target proteins.
Recent studies of our lab suggested that loss of E6AP results in the inhibition of Calcium/Calmodulin-dependent protein kinase II (CaMKII), enzyme that play a critical role in neuronal function and synaptic plasticity.

Nonetheless, the link between E6AP and CaMK2 regulation remains elusive, hampering the development of mechanism-based therapeutic strategies to ameliorate the neurological deficits of AS patients. It is even more questionable if it is worthwhile to investigate mechanism-based therapeutic strategies at all, since it is currently unknown to what extent the neurological symptoms are reversible.

Hence we propose to use an inducible AS mouse model (Ube3aLox-Stop/CreER mice), generated in our lab, to test the role of E6AP in brain development as well as adult neuronal function and, by switching the UBE3A gene on at any desirable age, we will investigate if there is a critical period for UBE3A expression and test, with behavioural and electrophysiological assays, if the neurological symptoms can be reversed.
Although not offering a specific therapeutic intervention for patients, this work provides imperative proof of principle that a putative treatment is still effective (or not) after the onset of the neurological symptoms.