Dynamic shift in localization of UBE3A across developmental stages in an Angelman syndrome mouse model.

The ubiquitin-proteasome pathway (UPP) plays a crucial role in cellular homeostasis by regulating protein degradation. UBE3A, an E3 ubiquitin ligase encoded by the UBE3A gene, is maternally expressed in neurons and linked to neurodevelopmental disorders such as Angelman syndrome (AS) and 15q11-q13 duplication syndrome (Dup15q syndrome). While UBE3A is predominantly nuclear in mature neurons, its dynamic subcellular localization across development and potential mitochondrial role remain poorly understood. Here, we investigate the developmental distribution of UBE3A among nuclear, mitochondrial, and cytosolic compartments in wild-type (WT) and AS mouse brains at embryonic (E16.5), early postnatal (P2), and adult stages. In wild-type neurons, UBE3A is initially distributed evenly across the cytoplasm, mitochondria, and nucleus at E16.5, but later shifts predominantly to the nucleus in adulthood, with a concomitant decline in mitochondrial localization. In contrast, UBE3A in AS shows an aberrant distribution at early developmental stages, reduced nuclear localization and enhanced cytosolic accumulation, and an altered developmental trajectory, with a persistent redistribution toward the cytosol and reduced nuclear accumulation. Our findings provide new insights into the developmental dynamic shift of UBE3A's subcellular localization and suggest a link between UBE3A dysfunction, mitochondrial abnormalities, and AS pathophysiology. Furthermore, these results suggest that in normal conditions, UBE3A has a functional role in mitochondria during early neurodevelopment, which may be disrupted in AS.