Investigating Ube3a-dependent sumoylation imbalance in the pathogenesis of the Angelman syndrome and autism

Neurodevelopmental and psychiatric disorders affect millions of people in the world and are a major socio-economic burden. Thanks to recent advances in sequencing technologies, the identification of genetic defects is becoming increasingly efficient, and has revealed the heterogeneous and complex etiology of these disorders. Yet, given the multifactorial origin of these diseases, the underlying cellular and molecular underpinnings are not known. Consequently, there are almost no effective therapies available. This research program focuses on two neurodevelopmental diseases caused by genetic alterations of UBE3A gene, which encodes an E3 ubiquitin ligase with transcriptional regulatory functions. Loss of UBE3A causes the Angelman syndrome (AS), characterized by developmental delay, speech impairments, intellectual disability and epilepsy, while duplications and triplications of UBE3A chromosomal locus are the most common cytogenetic events associated with Autism Spectrum Disorders (ASD). The pathophysiology of these disorders remains largely unclear and an effective treatment is lacking. We take an interdisciplinary approach that integrates the use of a wide range of genetic tools with proteomics and advanced imaging to dissect the pathological mechanism of AS and ASD. The relevance of our observations will be also validated in human neurons from reprogrammed and differentiated induced pluripotent stem cells (iPSCs) obtained from AS patients. We anticipate that the innovative and original nature of this research program will uncover novel pathogenic insights into the development of AS and ASD and hopefully offer new therapeutic perspectives to treat these as yet incurable diseases.