Hasiera » Seminars » Angelman Syndrome causing UBE3A ligase displays predominantly synaptic ubiquitination activity in the mouse brain

Angelman Syndrome causing UBE3A ligase displays predominantly synaptic ubiquitination activity in the mouse brain

Ugo Mayor

Ikerbasque - UPV/EHU (Leioa)

05 May 2023 13:00

Aketxe Room, Sede Building, Leioa

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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. The underlying genetic basis of AS, and the phenotypes observed in both humans and in animal models of AS, have previously been extensively described. However, the molecular mechanisms regulated by UBE3A ubiquitination in the brain remain highly elusive. Previous studies have reported a number of proteins whose abundance or activity are altered in AS models, implicating various signalling pathways in the physiopathology of AS. However, the identified pathways could well be altered further downstream of UBE3A ubiquitination events. We provide the first proteomic report of UBE3A-mediated ubiquitination events in a mammalian brain. For this we have combined the bioUb mouse model with a new mouse strain moderately increasing UBE3A levels. Several proteins known to be involved in the trafficking and maintenance of neurotransmitter receptors as well as proteins relaying the signals of these synaptic receptors are shown here to be ubiquitinated by UBE3A. The identified proteins have roles in higher mental function, long term potentiation, seizures and neurodevelopmental disorders, being involved in the BDNF, RAS/ERK and TSC/mTOR signalling pathways. A reduced ubiquitination of these proteins is expected when UBE3A levels are lower, so their identification could be key to opening novel therapeutic strategies for treating Angelman Syndrome. Further work will be required to characterize how UBE3A timely orchestrates each of these multiple regulatory events in different neuronal subtypes within the human brain.

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