Investigating the roles of UBE3A and TRPML1 in extracellular vesicle regulation to understand Angelman syndrome pathogenesis

Western University Of Health Sciences, Pomona CA

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Abstract

Brain development is a complex process involving intricate molecular interactions, which lead to alterations at the synaptic, neuronal, and circuit levels. Abnormalities in this process result in various forms of neurodevelopmental disorders. Angelman syndrome (AS) is a rare neurodevelopmental disorder with severe developmental delay, lack of language skills, severe cognitive impairment, motor dysfunction, and often with comorbid epilepsy and autism spectrum disorder (ASD). Genetic/genomic studies have attributed the cause of AS to deficiency of UBE3A, an imprinted gene, in neurons. Mice with maternal Ube3a deficiency recapitulate most of AS symptoms, and studies with these mouse models have revealed that Ube3a deficiency affects many brain regions and circuits. On the other hand, UBE3A overexpression or gain-of-function mutations have been linked to increased risk for autism spectrum disorders. Thus, accumulating evidence indicates that UBE3A plays critical roles in brain development and maturation. However, there is still a critical need for better understanding the roles of UBE3A during development and in adulthood. Emerging evidence also shows that the lysosomal cation channel, TRPML1, is also crucial for normal brain development and functions, since its deficiency results in a developmental neurological disease, muculipdosis type IV (MLIV). In recent years, extracellular vesicles (EVs), have been shown to play diverse roles in brain development and functions, in health and disease, through intercellular communication and transport of molecules. The proposed studies will test the hypothesis that UBE3A regulates dendritic spine development through TRPML1-mediated EV release, and that UBE3A deficiency leads to reduced EV release, resulting in abnormal dendritic spine development and maturation. The proposed studies will further test the hypothesis that treatment with EVs from wild-type neurons could rescue dendritic spine deficiency in AS neurons. The outcomes of this proposal will not only shed light on the roles of UBE3A and TRPML1 in neuronal development through the regulation of EV release but also provide novel approaches for the therapeutic treatment of AS patients. As emerging research indicates that EVs are suitable biomarkers and potential therapeutical tools for several neurological disorders, the outcomes of this proposal could have broad clinical implications.