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 Ebeling; Ben Distel; Ype Elgersma; Ravi Jagasia

doi:10.1016/j.xcrm.2021.100360

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 journal › Article › Academic › peer-review

31 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 language	English
Article number	100360
Journal	Cell Reports Medicine
Volume	2
Issue number	8
DOIs	https://doi.org/10.1016/j.xcrm.2021.100360
Publication status	Published - 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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Pandya, N. J., Wang, C., Costa, V., Lopatta, P., Meier, S., Zampeta, F. I., Punt, A. M., Mientjes, E., Grossen, P., Distler, T., Tzouros, M., Martí, Y., Banfai, B., Patsch, C., Rasmussen, S., Hoener, M., Berrera, M., Kremer, T., Dunkley, T., ... Jagasia, R. (2021). Secreted retrovirus-like GAG-domain-containing protein PEG10 is regulated by UBE3A and is involved in Angelman syndrome pathophysiology. Cell Reports Medicine, 2(8), Article 100360. https://doi.org/10.1016/j.xcrm.2021.100360

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title = "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 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.",

author = "Pandya, {Nikhil J.} and Congwei Wang and Veronica Costa and Paul Lopatta and Sonja Meier and Zampeta, {F. Isabella} and Punt, {A. Mattijs} and Edwin Mientjes and Philip Grossen and Tania Distler and Manuel Tzouros and Yasmina Mart{\'i} and Balazs Banfai and Christoph Patsch and Soren Rasmussen and Marius Hoener and Marco Berrera and Thomas Kremer and Tom Dunkley and Martin Ebeling and Ben Distel and Ype Elgersma and Ravi Jagasia",

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{\textquoteright}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: {\textcopyright} 2021 The Authors",

year = "2021",

month = aug,

day = "17",

doi = "10.1016/j.xcrm.2021.100360",

language = "English",

volume = "2",

journal = "Cell Reports Medicine",

publisher = "Cell Press",

number = "8",

}

Pandya, NJ, Wang, C, Costa, V, Lopatta, P, Meier, S, Zampeta, FI, Punt, AM, Mientjes, E, Grossen, P, Distler, T, Tzouros, M, Martí, Y, Banfai, B, Patsch, C, Rasmussen, S, Hoener, M, Berrera, M, Kremer, T, Dunkley, T, Ebeling, M, Distel, B , Elgersma, Y & Jagasia, R 2021, 'Secreted retrovirus-like GAG-domain-containing protein PEG10 is regulated by UBE3A and is involved in Angelman syndrome pathophysiology', Cell Reports Medicine, vol. 2, no. 8, 100360. https://doi.org/10.1016/j.xcrm.2021.100360

TY - JOUR

T1 - Secreted retrovirus-like GAG-domain-containing protein PEG10 is regulated by UBE3A and is involved in Angelman syndrome pathophysiology

AU - Pandya, Nikhil J.

AU - Wang, Congwei

AU - Costa, Veronica

AU - Lopatta, Paul

AU - Meier, Sonja

AU - Zampeta, F. Isabella

AU - Punt, A. Mattijs

AU - Mientjes, Edwin

AU - Grossen, Philip

AU - Distler, Tania

AU - Tzouros, Manuel

AU - Martí, Yasmina

AU - Banfai, Balazs

AU - Patsch, Christoph

AU - Rasmussen, Soren

AU - Hoener, Marius

AU - Berrera, Marco

AU - Kremer, Thomas

AU - Dunkley, Tom

AU - Ebeling, Martin

AU - Distel, Ben

AU - Elgersma, Ype

AU - Jagasia, Ravi

N1 - 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

PY - 2021/8/17

Y1 - 2021/8/17

N2 - 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.

AB - 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.

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U2 - 10.1016/j.xcrm.2021.100360

DO - 10.1016/j.xcrm.2021.100360

M3 - Article

C2 - 34467244

AN - SCOPUS:85112860337

VL - 2

JO - Cell Reports Medicine

JF - Cell Reports Medicine

IS - 8

M1 - 100360

ER -

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

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