Synaptic dysfunction in Angelman syndrome: spatio-temporal trajectories and molecular mechanisms

Angelman Syndrome (AS) is a severe genetic disorder of neurodevelopmental origin, causing serious learning difficulties, speech problems, motor delay, behavioral alterations and epilepsy. It is caused by defects of the UBE3A gene. While the genetic cause is well-known, our knowledge on how the missing gene leads to clinical symptoms remains elusive, limiting current treatments and the development of new ones aimed at correcting pathways downstream UBE3A. Our project will tackle this question and investigate how UBE3A works in the brain and how its absence causes AS. This research program is supported by strong data obtained in our laboratory showing that UBE3A is crucial for building synapses, the elementary functional units of the brain, where information is transmitted throughout the nervous system. To empower this knowledge, we will test the hypothesis that UBE3A possesses specific roles in specific brain regions and cell types, which we hope could allow to link UBE3A loss in distinct brain circuits to specific clinical deficits. Furthermore, we will also consider another important aspect of UBE3A biology, that is the presence of different "versions" of UBE3A (isoforms), whose function is not known yet. AS is a neurodevelopmental disorder, which manifests very early in life. It is therefore crucial to detect the earliest impairments that are directly caused by UBE3A loss. If targeted, they should result in more effective treatments. Thus, the knowledge generated in this project will be informative for developing novel therapies that could ameliorate the quality of life of AS individuals and their families.