UBE3A reinstatement restores behavior and proteome in an Angelman Syndrome mouse model of Imprinting Defects

Abstract

Angelman Syndrome (AS) is a severe neurodevelopmental disorder with only symptomatic treatment currently available. Besides mutations within theUBE3Agene, AS is caused by deletions, imprinting center defects (mICD) or uniparental disomy of chromosome 15 (UPD). Current mouse models areUbe3a-centric and do not address expression changes of other 15q11-q13 genes on AS pathophysiology. Here, we studied a mouse line that harbors a mutation affecting the AS-PWS imprinting center, hence modeling mICD/UPD AS subtypes. mICD mice showed significant reduction in UBE3A protein, bi-allelic expression ofUbe3a-ATSandMkrn3-Snord115gene cluster, leading to robust AS behavioral deficits and proteome alterations similar toUbe3aKO mice. Genetic UBE3A overexpression in mICD mice, mimicking therapeutic strategies that effectively activate the biallelic silencedUbe3agene, resulted in a complete rescue of all behavioral and proteome alterations. Subsequently, treatment with an antisense oligonucleotide (ASO) to directly activate the biallelic silencedUbe3agene in mICD mice also resulted in efficient reinstatement of UBE3A, alongside a partial rescue of behavioral phenotypes. Taken together, these findings demonstrate that UBE3A loss is the primary factor underlying AS phenotypes in the mICD/UPD mouse model, and also corroborate that UBE3A reinstatement is an attractive therapeutic strategy for mICD/UPD AS individuals.