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.
Krzeski et al. (Fri,) studied this question.