Stem-cell modeling of cerebellar dysfunction of Angelman syndrome

Abstract

Angelman syndrome is a severe neurodevelopmental disorder caused by loss of function of the maternal allele of the neuron-specific imprinted gene UBE3A. Although Angelman syndrome presents with developmental delay, ataxia, epilepsy, and speech impairment, the contribution of specific brain regions, particularly the cerebellum, remains unclear. To address this, we developed a stem cell-based model of regionally patterned human cerebellar organoids derived from Angelman syndrome patient-induced pluripotent stem cells carrying class II deletions and unrelated unaffected control lines, followed by maturation in two-dimensional cultures. These cerebellar organoids recapitulate cerebellar lineage specification and neuron-specific UBE3A imprinting. Angelman syndrome organoids display reduced size, impaired neuroepithelial expansion, and decreased expression of progenitor markers. At later stages, transcriptomic and functional analyses reveal delayed neuronal maturation, enrichment of apoptosis-related pathways, and altered network activity, including enhanced excitability. Together, these findings establish cerebellar organoids as a relevant platform for future mechanistic studies of cerebellar dysfunction in Angelman syndrome and therapeutic screening aimed at targeting cerebellar dysfunction in this disease. Cerebellar differentiation of Angelman syndrome patient-derived iPSC lines shows impaired early progenitor expansion and delayed neuronal maturation, leading to disease-specific impairments in neuronal activity and survival.