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

Nikhil J. Pandya*, Congwei Wang, Veronica Costa, Paul Lopatta, Sonja Meier, F. Isabella Zampeta, A. Mattijs Punt, Edwin Mientjes, Philip Grossen, Tania Distler, Manuel Tzouros, Yasmina Martí, Balazs Banfai, Christoph Patsch, Soren Rasmussen, Marius Hoener, Marco Berrera, Thomas Kremer, Tom Dunkley, Martin EbelingBen Distel, Ype Elgersma, Ravi Jagasia*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

6 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article number100360
JournalCell Reports Medicine
Volume2
Issue number8
DOIs
Publication statusPublished - 17 Aug 2021

Bibliographical note

Funding Information:
We would like to thank Children's Hospital in Boston, under the leadership of Prof. Christopher Walsh, for recruitment of patients into the study; Harvard iPSC core facility and the team of Laurence Daheron for the reprogramming and quality control of hiPSC lines; Prof. Michael Greenberg for expertise and brainstorming on modeling AS in hiPSC; R. Schmucki and F. Koechl for help with RNA-seq analysis; D. Avilla, P. Jakob, and S. Golling for help with LC-MS data acquisition; the Roche postdoctoral fellowship program for funding N.J.P. C.W. and P.G. and the Roche RiSE internship program for funding S.M. V.C. N.J.P. Y.M. and P.L. performed the neuronal differentiations. N.J.P. and M.T. planned and performed the proteomics experiments. N.J.P. P.L. and S.M. planned and performed the immunostaining experiments. N.J.P. C.W. and T.D. planned and performed the RNA experiments. P.G. and N.J.P. performed the EV work. M.E. M.B. and B.B. performed the data analysis. A.M.P. performed the bacterial ubiquitination assays. F.I.Z. performed the Y2H and migration assays. E.M. performed the brain analysis. T.D. Y.E. M.H. M.E. B.D. M.T. V.C. C.P. and R.J. supervised the research. N.J.P. B.D. Y.E. and R.J. wrote the manuscript. All of the authors reviewed the manuscript. N.J.P. V.C. C.W. P.L. S.M. P.G. T.D. M.T. Y.M. B.B. C.P. S.R. M.H. M.B. T.K. T.D. M.E. and R.J. are employed by F. Hoffmann-La Roche. Parts of the work in this study have been filed in the patent WO2020/148310. The remaining authors declare no competing financial interests.

Funding Information:
We would like to thank Children’s Hospital in Boston, under the leadership of Prof. Christopher Walsh, for recruitment of patients into the study; Harvard iPSC core facility and the team of Laurence Daheron for the reprogramming and quality control of hiPSC lines; Prof. Michael Greenberg for expertise and brainstorming on modeling AS in hiPSC; R. Schmucki and F. Koechl for help with RNA-seq analysis; D. Avilla, P. Jakob, and S. Golling for help with LC-MS data acquisition; the Roche postdoctoral fellowship program for funding N.J.P., C.W., and P.G. and the Roche RiSE internship program for funding S.M.

Publisher Copyright:
© 2021 The Authors

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