UBE3A-induced ubiquitination changes in the brain reveal the molecular complexity of Angelman syndrome

Angelman Syndrome (AS) is a neurodevelopmental disorder with complex symptomatology caused by the loss of maternal allele expression of one single gene in the brain, the ubiquitin E3 ligase UBE3A. Even if the underlying genetic basis of AS has previously been extensively described, the molecular mechanisms regulated by UBE3A ubiquitination in the brain remain highly elusive. Here we provide the first proteomic report of UBE3A-mediated ubiquitination events in a mammalian brain. In order to identify Ube3a substrates, we have combined our previously described bioUb mouse with a new mouse strain with slightly elevated UBE3A levels. Proteomic comparison of the ubiquitinated material between wild-type and Ube3a over-expressing mice shows several proteins to be ubiquitinated by UBE3A. Some of those proteins are known to be involved in the trafficking and maintenance of neurotransmitter receptors, as well as relaying the signals of these synaptic receptors. The identified proteins have roles in higher mental function, long term potentiation, seizures and neurodevelopmental disorders, and are involved in the BDNF, RAS/ERK and TSC/mTOR signalling pathways. A reduced ubiquitination of these proteins is expected when UBE3A levels are low, so their identification could be key to opening novel therapeutic strategies for treating AS.