UBE3A isoform-selective and non-selective contributions to Angelman syndrome phenotypes

Angelman syndrome (AS) is a neurodevelopmental disorder caused by UBE3A loss. In humans, UBE3A generates three isoforms that localize to distinct subcellular compartments-one mainly nuclear and two cytoplasmic. The nuclear and most highly expressed cytoplasmic UBE3A isoform are highly conserved in mice, whereas the cytoplasmic human isoform accounting for just ~1% of total UBE3A has no mouse counterpart. Loss of the nuclear-enriched UBE3A isoform causes AS and behavioral deficits in mice; no specific contribution of the predominant cytoplasmic UBE3A isoform has yet been identified. Because the nuclear-enriched isoform constitutes ~80% of total UBE3A protein, it is unclear if its outsized phenotypic impact upon deletion is due to a loss of nuclear UBE3A function or simply a dramatic reduction in overall UBE3A levels. If the former, overexpression of the cytoplasmic UBE3A isoform would be unable to rescue AS phenotypes. To test this, we developed a mouse model that overexpresses the cytoplasmic UBE3A isoform (mIso2-OE) and crossed it with an AS mouse model to yield wildtype (WT), mIso2-OE, AS, and AS/mIso2-OE mice, the latter of which lacked the endogenous nuclear UBE3A isoform (mIso3) in neurons. Unexpectedly, we found that overexpression of the cytoplasmic UBE3A isoform alone rescued most tested AS-related behavioral deficits, except for kindling-induced epileptogenesis or seizure-linked perineuronal net (PNN) accumulation in AS mice. Thus, while many AS phenotypes may be caused by isoform non-selective reductions in UBE3A levels, AS-associated epilepsies appear linked to isoform-selective nuclear UBE3A loss. This information is expected to inform AS gene therapy studies.