Secreted retrovirus-like GAG-domain-containing protein PEG10 is regulated by UBE3A and is involved in Angelman syndrome pathophysiology

Angelman syndrome (AS) is a neurodevelopmental disorder caused by the loss of maternal UBE3A, a ubiquitin protein ligase E3A. Here, we study neurons derived from patients with AS and neurotypical individuals, and reciprocally modulate UBE3A using antisense oligonucleotides. Unbiased proteomics reveal proteins that are regulated by UBE3A in a disease-specific manner, including PEG10, a retrotransposon-derived GAG protein. PEG10 protein increase, but not RNA, is dependent on UBE3A and proteasome function. PEG10 binds to both RNA and ataxia-associated proteins (ATXN2 and ATXN10), localizes to stress granules, and is secreted in extracellular vesicles, modulating vesicle content. Rescue of AS patient-derived neurons by UBE3A reinstatement or PEG10 reduction reveals similarity in transcriptome changes. Overexpression of PEG10 during mouse brain development alters neuronal migration, suggesting that it can affect brain development. These findings imply that PEG10 is a secreted human UBE3A target involved in AS pathophysiology. [Display omitted] Proteomic analysis of Angelman hIPSC-derived neurons reveals UBE3A targetsPEG10 protein is reciprocally modulated by UBE3A using antisense oligonucleotidesPEG10 regulates extracellular vesicle proteome and neuronal transcriptome Pandya et al. use proteomic analysis on antisense oligonucleotides-treated control and Angelman syndrome pluripotent stem-cell-derived neurons to reciprocally modulate UBE3A levels and identify PEG10. PEG10 is a GAG domain-containing extracellular vesicle protein involved in modulating EV proteome and neuronal transcriptome downstream of UBE3A.