Loss ofUBE3Aimpacts both neuronal and non-neuronal cells in human cerebral organoids

Abstract

Angelman syndrome is a neurodevelopmental disorder caused by (epi)genetic lesions of maternalUBE3A. Research has focused largely on the role ofUBE3Ain neurons due to its imprinting in that cell type. Yet, evidence suggests there may be broader neurodevelopmental impacts ofUBE3Adysregulation. Human cerebral organoids might reveal these understudied aspects ofUBE3Aas they recapitulate diverse cell types of the developing human brain. We performed scRNAseq on organoids to reveal the effects ofUBE3Adisruption on cell type-specific compositions and transcriptomic alterations. In the absence ofUBE3A, progenitor proliferation and structures were disrupted while organoid composition shifted away from proliferative cell types. We observed impacts on non-neuronal cells, including choroid plexus enrichment. Furthermore, EMX1+ cortical progenitors were negatively impacted, disrupting corticogenesis, and potentially delaying excitatory neuron maturation. This work reveals novel impacts ofUBE3Aon understudied cell types and related neurodevelopmental processes and elucidates potential new therapeutic targets.TeaserHuman cerebral organoids exhibit compositional and transcriptomic alterations in both neuronal and non-neuronal cells in the absence ofUBE3A.