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

Abstract

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.

Characterizing spine issues: If offers novel therapeutics to Angelman syndrome

“…The density of the spine in the very early stage of synaptogenesis is relatively normal or even increase in Ube3a maternal deleted neurons upon activity stimulus (Greer et al, 2010; Sell et al., 2019), more spines are eliminated during the critical period (Kim et al, 2016). In the adult, more immature spines and less mature spines in Ube3a maternal deleted neurons were visualized (Kim et al, 2016; Wang, Lou, et al, 2019). One may in‐depth measure the spine formation and maturation process in cultured neurons through the in vitro live imaging system.…”

“…Early embryonic deletion but not delayed deletion (during and after critical period, P21‐adult) of Ube3a in mice recapitulated the main behaviors defects of AS (Sonzogni et al., 2019), and late reinstatement of Ube3a have minimal benefits to AS phenotypes (Huang et al., 2012; Meng et al., 2015; Rotaru et al., 2018; Silva‐Santos et al., 2015), strengthened the critical roles of Ube3a during early development. It is coincident with the decreased spine density and less maturation visualized by in vivo two‐photon microscopy and Golgi staining during critical period and adulthood (Dindot et al, 2008; Kim et al, 2016; Santo & Stryker, 2010; Sun, Liu, et al, 2015; Hethorn et al., 2015; Sun et al., 2016, 2018; Wang, Lou, et al, 2019; Yashiro et al., 2009). Since the complexity and time‐cost‐consuming by in vivo behaviors screening (Sonzogni et al., 2018), a powerful in vitro screening system may speedup the investigation of AS pathophysiology and therapeutics.…”

“…From the three brain regions analyzed, hippocampus, cortex and cerebellum, spine density was decreased in the deleted animals (Dindot et al, 2008). It was later confirmed the decreased spine density by the following studies in adult maternal Ube3a deletion mice (Hethorn et al., 2015; Sun et al, 2018; Sun, Liu, Moreno, Baudry, & Bi, 2015b; Sun et al., 2016; Wang, Lou, et al, 2019). Moreover, the maturation of the spine was found impaired.…”

“…Moreover, the maturation of the spine was found impaired. In the Ube3a deleted animals, a higher frequency of long and thin spines and a reduction of mature spines were found in cerebellar Purkinje cells, the apical dendrites of hippocampal CA1 pyramidal neurons, and the basal dendrites of layer 2/3 pyramidal neurons of motor cortex and primary somatosensory cortex (Wang, Lou, et al, 2019). However, through crossing with Thy1‐GFP, the spine density was found increased in hippocampal CA1 pyramidal neurons in vivo and in vitro, which could be rescued by genetically suppressing the Ube3a substrate Ephexin5 (Sell et al., 2019).…”

Ubiquitin and Ubiquitin-Like Proteins in the Critical Equilibrium between Synapse Physiology and Intellectual Disability

“…Data from AS mouse models suggest that UBE3A plays a key role in modulating synaptic pathways important for cognition and behavior. Neurons from Ube3a-KO mice display abnormal dendritic spines, reduced excitatory neurotransmission and impaired synaptic plasticity (Dindot et al, 2008;Yashiro et al, 2009;Pignatelli et al, 2014;Kim et al, 2016;Avagliano Trezza et al, 2019;Wang et al, 2019a). Given the primary function of UBE3A as E3 ubiquitin ligase, defective ubiquitination is thought to be at the basis of neuronal dysfunctions and clinical manifestations of AS.…”