UBE3A modulates Angelman syndrome transcriptome via retrovirus like GAG domain containing protein PEG10

Angelman syndrome (AS) is a rare severe neurodevelopmental disorder caused by neuronal loss of ubiquitin ligase UBE3A. Despite therapies for AS that reinstate the paternal UBE3A allele entering clinics, our understanding of relevant UBE3A targets particularly in humans has been severely limited. We established human patient derived neuron (hiPSC) models for AS and demonstrate specific and reciprocal modulation of UBE3A using anti-sense oligonucleotides (ASOs) in AS patient derived neurons. Through unbiased proteomic analysis we identified UBE3A targets, including the novel human specific retrotransposon derived GAG domain containing protein PEG10. PEG10 protein but not RNA was elevated in AS hiPSC-derived neurons as well in an AS patient brain. Its upregulation in AS was proteasome and UBE3A dependent. Functional analysis revealed that PEG10 binds both RNA and ataxia associated proteins, ATXN2 and ATXN10. PEG10 localizes to stress granules and is secreted in extracellular vesicles where it affects vesicle content in AS neurons. AS neurons in which either UBE3A was reinstated or PEG10 was reduced, showed a striking similarity in transcriptome changes implicating PEG10 as a central driver in transcriptomic alterations downstream of UBE3A. Subsequently, overexpression of human PEG10 in mice dramatically affected cortical neuronal migration. These findings imply that PEG10 is a secreted UBE3A target involved inAS pathophysiology.