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

ABSTRACT: Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by mutations that effect expression of the maternal UBE3A allele, which encodes the ubiquitin protein ligase E3A (UBE3A). Although several potential UBE3A targets have been identified, our understanding of relevant disease targets is very limited, and validation in patient-derived cells is lacking. We established human iPSC (hiPSC) control and AS patient-derived neuronal models and demonstrate specific and reciprocal modulation of UBE3A using anti-sense oligonucleotides (ASOs). Through unbiased proteomic analysis we identified proteins whose abundance were directly affected by manipulating UBE3A levels, including the novel human specific PEG10 protein, a secreted retrotransposon derived GAG domain-containing protein. PEG10 protein, but not RNA, was elevated in AS hiPSC-derived neurons as well as in postmortem AS brain tissue, and we showed that its upregulation in patient-derived cells is dependent on both UBE3A and normal proteasome function. 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 regulates vesicle content. AS patient-derived neurons in which either UBE3A was reinstated or PEG10 was reduced, showed a striking similarity in transcriptome changes. In addition, overexpression of PEG10 during mouse brain development affected the migration of the PEG10-overexpressing neurons, suggesting that PEG10 overexpression can affect neuronal function at a critical time during brain development. Taken together these findings imply that PEG10 is a novel secreted UBE3A target, and is involved in AS pathophysiology.

INSTRUMENT(S): Orbitrap Fusion Lumos, Orbitrap Fusion

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Nikhil J. Pandya  

PROVIDER: MSV000087654 | MassIVE | Fri Jun 18 05:25:00 BST 2021

REPOSITORIES: MassIVE