Targeting UBE3A and downstream estrogen receptor-β signaling to restore oligodendroglial homeostasis in Angelman syndrome

Mutations that reduce UBE3A cause Angelman syndrome (AS), a neurodevelopmental disorder marked by severe developmental delay and neuropsychiatric symptoms. Although UBE3A has been studied primarily in neurons, it is also expressed in the oligodendrocyte lineage, raising the possibility that glial dysfunction contributes to disease phenotypes. Here we identify an intrinsic, UBE3A-dependent mechanism that governs oligodendrocyte precursor cell (OPC) homeostasis, a process necessary for normal myelination. Using human iPSC-derived OPCs, we performed a targeted compound screen and found that loss of UBE3A diminishes estrogen receptor-{beta} (ESR{beta}) signaling, leading to impaired OPC self-renewal. Mechanistically, UBE3A sustains ESR{beta} levels in OPCs and thereby maintains downstream signaling required for OPC proliferation and stable OPC density. To address cell-type specificity and neuron-glia interactions, we combined oligodendrocyte-lineage-restricted Ube3a knockdown in vivo with reductionist iPSC neuron-OPC co-culture assays, which together support an intrinsic requirement for oligodendroglial UBE3A in OPC proliferation and myelination. Pharmacologic activation of ESR{beta} with selective agonists restored OPC self-renewal and myelination deficits in AS patient iPSC-based systems and rescued oligodendroglial and behavioral abnormalities in AS mouse models. Notably, ESR{beta} signaling primarily regulates OPC homeostasis rather than directly driving oligodendrocyte differentiation, pinpointing a stage-specific therapeutic entry point. These findings highlight a tractable oligodendroglial pathway downstream of UBE3A with translational potential for AS. One Sentence SummaryUBE3A regulates oligodendroglial homeostasis for myelination via estrogen receptor-{beta} signaling as a therapeutic target for Angelman syndrome.