Dysfunction of the Autophagy System and MDM2-p53 Axis Leads to the Accumulation of Amyloidogenic Proteins in Angelman Syndrome Models

Angelman Syndrome (AS) is a neurodevelopmental disorder caused by the deficiency of the UBE3A gene that for a E3 ligase protein part of the ubiquitin-proteasome system (UPS). Autophagy and UPS systems remove abnormal proteins, but any dysfunction in these processes can affect neuronal development and wellbeing. Herein, the involvement of the UPS/autophagy system in the regulation of intracellular signaling pathways related to toxic protein accumulation was investigated in cellular and mice AS models, silenced for UB3A (UB3A-). The main findings are as follows: i)autophagy markers were upregulated in UBE3A- cells respect to control cells; ii)a dysregulation of AKT/mTOR pathway, which is linked to autophagy/synaptic development, was evidenced in cellular and animal models of AS with respect to controls; iii) the ubiquitin ligase MDM2 was downregulated, and the tumor suppressor p53, normally inhibited by MDM2, enhanced its expression and transcriptional activity in UB3A-cells with respect to controls. Finally, UB3A-cells presented a significant alteration in the levels of β-amyloids with respect to control cells, and a reduction of α-synuclein levels, typical of neurodevelopmental disorder. Overall, these data suggest that AS models presented altered signaling pathway related to autophagy/UPS systems, potentially leading to the accumulation of toxic proteins that impact synaptic development.