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Significance Deletion or loss-of-function mutations of the maternally inherited allele ofUBE3A , which encodes an E3 ubiquitin ligase, lead to Angelman syndrome (AS), a developmental neurological disorder with severe intellectual disability. The consequences ofUBE3A dysfunction are not well understood. Here, we demonstrate that UBE3A ubiquitinates PTPA, an activator of protein phosphatase 2A. Maternal loss ofUbe3a in an AS mouse model leads to significant increases in PTPA level and PP2A activity. Genetic reduction of PTPA or pharmacologic inhibition of PP2A in an AS mouse model alleviated the deficits in dendritic spine morphology and synaptic transmission and improved behavioral phenotypes. These data suggest a critical role of UBE3A-PTPA-PP2A signaling in the pathogenesis of UBE3A-related disorders.

UBE3A-mediated PTPA ubiquitination and degradation regulate PP2A activity and dendritic spine morphology