02153nas a2200301   4500000000100000000000100001008004100002260001500043653001800058653002300076100001900099700002200118700002900140700002000169700002900189700001700218700002000235700002100255700002000276700001800296700002300314700002300337700002300360245007000383856005500453520132900508022001401837       2026                            d  c2026-09-2810adisease model10aMolecular medicine1 aCarina Maranga1 aAdriana A. Vieira1 aJoão Camões dos Santos1 aTeresa P. Silva1 aJoana Gonçalves-Ribeiro1 aKarim Chebli1 aMiguel Casanova1 aMaud Borensztein1 aLaura Steenpass1 aSandra H. Vaz1 aTiago G. Fernandes1 aSimão T. da Rocha1 aEvguenia P. Bekman00aStem-cell modeling of cerebellar dysfunction of Angelman syndrome  uhttps://www.nature.com/articles/s42003-026-11008-y3 aAngelman 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.  a2399-3642