Individuals with a deletion of chromosome 15q11-q13 suffer from Angelman syndrome (AS), a neurogenetic developmental disorder characterized by intellectual disability, motor ataxia, absent speech, and seizures. The specific gene that is responsible for AS encodes the ubiquitin protein ligase UBE3A. In AS, deficits in synaptic signaling and plasticity appear to play a critical role in the disease phenotype, but the exact functional role of UBE3A and its relevant downstream targets are unknown. In order to develop appropriate treatments for AS, it is necessary to understand the pathophysiological changes caused by UBE3A deletion. Until recently it has not been possible to examine the functional properties of brain neurons in affected individuals. The discovery of genomic reprogramming of human somatic cells into induced pluripotent stem cell (iPSC) lines provides a novel way to model human diseases with complex genetics. We have recently succeeded in reprogramming dermal fibroblasts from AS patients, as well as age-matched control subjects, into iPSCs, and then differentiated these cells into functional neurons that maintain the imprinting phenotype of UBE3A expression seen in AS patients. We are now poised to take advantage of these novel patient-derived cell lines to test specific hypotheses about the underlying physiological defects in AS.
The first aim uses electrophysiological and immunocytochemical approaches to explore the intrinsic functional properties of iPSC-derived neurons and activity-dependent plasticity of synaptic connections. Rescue experiments will focus on the roles of the immediate early gene ARC and the calcium/calmodulin-dependent protein kinase CaMKII in AS-associated deficits in synaptic signaling.
The second aim will explore changes in synapse number and dendritic spine density in AS-derived neurons. Rescue experiments will target the role of ephexin-5, a substrate of UBE3A that plays a role in regulating excitatory synapse number during development. Overall, this approach may prove useful for identifying novel targets for drug discovery and for screening potential therapeutics aimed at ameliorating and/or curing the seizures, movement disorders, and language and cognitive impairments in Angelman syndrome.
Angelman syndrome is a neurogenetic developmental disorder characterized by intellectual disability, motor ataxia, absent speech, and seizures. The proposed research uses a novel human stem cell culture model to investigate the cellular and molecular basis of these deficits. The long term objective is to identify novel therapeutic targets for treating Angelman syndrome and other autism-related disorders.