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

Abstract

Significance Deletion or loss-of-function mutations of the maternally inherited allele of UBE3A, which encodes an E3 ubiquitin ligase, lead to Angelman syndrome (AS), a developmental neurological disorder with severe intellectual disability. The consequences of UBE3A dysfunction are not well understood. Here, we demonstrate that UBE3A ubiquitinates PTPA, an activator of protein phosphatase 2A. Maternal loss of Ube3a 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. Deficiency in the E3 ubiquitin ligase UBE3A leads to the neurodevelopmental disorder Angelman syndrome (AS), while additional dosage of UBE3A is linked to autism spectrum disorder. The mechanisms underlying the downstream effects of UBE3A gain or loss of function in these neurodevelopmental disorders are still not well understood, and effective treatments are lacking. Here, using stable-isotope labeling of amino acids in mammals and ubiquitination assays, we identify PTPA, an activator of protein phosphatase 2A (PP2A), as a bona fide ubiquitin ligase substrate of UBE3A. Maternal loss of Ube3a (Ube3am−/p+) increased PTPA level, promoted PP2A holoenzyme assembly, and elevated PP2A activity, while maternal 15q11–13 duplication containing Ube3a down-regulated PTPA level and lowered PP2A activity. Reducing PTPA level in vivo restored the defects in dendritic spine maturation in Ube3am−/p+ mice. Moreover, pharmacological inhibition of PP2A activity with the small molecule LB-100 alleviated both reduction in excitatory synaptic transmission and motor impairment in Ube3am−/p+ mice. Together, our results implicate a critical role of UBE3A-PTPA-PP2A signaling in the pathogenesis of UBE3A-related disorders and suggest that PP2A-based drugs could be potential therapeutic candidates for treatment of UBE3A-related disorders.