Stem-cell modeling of cerebellar dysfunction of Angelman syndrome

Although AS presents with developmental delay, ataxia, epilepsy, and speech impairment, the distinct roles of various brain regions in its pathology remain unclear, hindering the design of effective therapeutic strategies. Of all brain regions, the nature and impact of dysfunction of the cerebellum in AS remain elusive.

To start addressing this, we leveraged our optimized stem cell-based model of regionally patterned human cerebellar organoids (hCerOs) capable of producing major cerebellar neuronal subtypes, including Purkinje and granule cells, further matured in a two-dimensional (2D) culture system. We modeled AS using induced pluripotent stem cell (iPSC) lines carrying the common class II deletion and unaffected controls previously validated in our system. hCerOs from both backgrounds recapitulate lineage commitment and neuron-specific UBE3A imprinting.