Loss of MAGEL2 in prader-willi syndrome leads to decreased secretory granule and neuropeptide production

Helen Chen; A. Kaitlyn Victor; Jonathon Klein; Klementina Fon Tacer; Derek J.C. Tai; Celine de Esch; Alexander Nuttle; Jamshid Temirov; Lisa C. Burnett; Michael Rosenbaum; Yiying Zhang; Li Ding; James J. Moresco; Jolene K. Diedrich; John R. Yates; Heather S. Tillman; Rudolph L. Leibel; Michael E. Talkowski; Daniel D. Billadeau; Lawrence T. Reiter; Patrick Ryan Potts

doi:10.1172/jci.insight.138576

Loss of MAGEL2 in prader-willi syndrome leads to decreased secretory granule and neuropeptide production

Helen Chen, A. Kaitlyn Victor, Jonathon Klein, Klementina Fon Tacer, Derek J.C. Tai, Celine de Esch, Alexander Nuttle, Jamshid Temirov, Lisa C. Burnett, Michael Rosenbaum, Yiying Zhang, Li Ding, James J. Moresco, Jolene K. Diedrich, John R. Yates, Heather S. Tillman, Rudolph L. Leibel, Michael E. Talkowski, Daniel D. Billadeau, Lawrence T. ReiterPatrick Ryan Potts

Research output: Contribution to journal › Article › peer-review

33 Scopus citations

Abstract

Prader-Willi syndrome (PWS) is a developmental disorder caused by loss of maternally imprinted genes on 15q11-q13, including melanoma antigen gene family member L2 (MAGEL2). The clinical phenotypes of PWS suggest impaired hypothalamic neuroendocrine function; however, the exact cellular defects are unknown. Here, we report deficits in secretory granule (SG) abundance and bioactive neuropeptide production upon loss of MAGEL2 in humans and mice. Unbiased proteomic analysis of Magel2^pΔ^/m+ mice revealed a reduction in components of SG in the hypothalamus that was confirmed in 2 PWS patient-derived neuronal cell models. Mechanistically, we show that proper endosomal trafficking by the MAGEL2-regulated WASH complex is required to prevent aberrant lysosomal degradation of SG proteins and reduction of mature SG abundance. Importantly, loss of MAGEL2 in mice, NGN2-induced neurons, and human patients led to reduced neuropeptide production. Thus, MAGEL2 plays an important role in hypothalamic neuroendocrine function, and cellular defects in this pathway may contribute to PWS disease etiology. Moreover, these findings suggest unanticipated approaches for therapeutic intervention.

Original language	English (US)
Article number	e138576
Journal	JCI Insight
Volume	5
Issue number	17
DOIs	https://doi.org/10.1172/jci.insight.138576
State	Published - Sep 3 2020
Externally published	Yes

ASJC Scopus subject areas

General Medicine

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Chen, H., Kaitlyn Victor, A., Klein, J., Tacer, K. F., Tai, D. J. C., de Esch, C., Nuttle, A., Temirov, J., Burnett, L. C., Rosenbaum, M., Zhang, Y., Ding, L., Moresco, J. J., Diedrich, J. K., Yates, J. R., Tillman, H. S., Leibel, R. L., Talkowski, M. E., Billadeau, D. D., ... Potts, P. R. (2020). Loss of MAGEL2 in prader-willi syndrome leads to decreased secretory granule and neuropeptide production. JCI Insight, 5(17), Article e138576. https://doi.org/10.1172/jci.insight.138576

Chen, H, Kaitlyn Victor, A, Klein, J, Tacer, KF, Tai, DJC, de Esch, C, Nuttle, A, Temirov, J, Burnett, LC, Rosenbaum, M, Zhang, Y, Ding, L, Moresco, JJ, Diedrich, JK, Yates, JR, Tillman, HS, Leibel, RL, Talkowski, ME, Billadeau, DD, Reiter, LT & Potts, PR 2020, 'Loss of MAGEL2 in prader-willi syndrome leads to decreased secretory granule and neuropeptide production', JCI Insight, vol. 5, no. 17, e138576. https://doi.org/10.1172/jci.insight.138576

@article{17fa192c2375480db9d75cc8f95913e5,

title = "Loss of MAGEL2 in prader-willi syndrome leads to decreased secretory granule and neuropeptide production",

abstract = "Prader-Willi syndrome (PWS) is a developmental disorder caused by loss of maternally imprinted genes on 15q11-q13, including melanoma antigen gene family member L2 (MAGEL2). The clinical phenotypes of PWS suggest impaired hypothalamic neuroendocrine function; however, the exact cellular defects are unknown. Here, we report deficits in secretory granule (SG) abundance and bioactive neuropeptide production upon loss of MAGEL2 in humans and mice. Unbiased proteomic analysis of Magel2pΔ/m+ mice revealed a reduction in components of SG in the hypothalamus that was confirmed in 2 PWS patient-derived neuronal cell models. Mechanistically, we show that proper endosomal trafficking by the MAGEL2-regulated WASH complex is required to prevent aberrant lysosomal degradation of SG proteins and reduction of mature SG abundance. Importantly, loss of MAGEL2 in mice, NGN2-induced neurons, and human patients led to reduced neuropeptide production. Thus, MAGEL2 plays an important role in hypothalamic neuroendocrine function, and cellular defects in this pathway may contribute to PWS disease etiology. Moreover, these findings suggest unanticipated approaches for therapeutic intervention.",

author = "Helen Chen and {Kaitlyn Victor}, A. and Jonathon Klein and Tacer, {Klementina Fon} and Tai, {Derek J.C.} and {de Esch}, Celine and Alexander Nuttle and Jamshid Temirov and Burnett, {Lisa C.} and Michael Rosenbaum and Yiying Zhang and Li Ding and Moresco, {James J.} and Diedrich, {Jolene K.} and Yates, {John R.} and Tillman, {Heather S.} and Leibel, {Rudolph L.} and Talkowski, {Michael E.} and Billadeau, {Daniel D.} and Reiter, {Lawrence T.} and Potts, {Patrick Ryan}",

note = "Publisher Copyright: {\textcopyright} 2020, Chen et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.",

year = "2020",

month = sep,

day = "3",

doi = "10.1172/jci.insight.138576",

language = "English (US)",

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T1 - Loss of MAGEL2 in prader-willi syndrome leads to decreased secretory granule and neuropeptide production

AU - Chen, Helen

AU - Kaitlyn Victor, A.

AU - Klein, Jonathon

AU - Tacer, Klementina Fon

AU - Tai, Derek J.C.

AU - de Esch, Celine

AU - Nuttle, Alexander

AU - Temirov, Jamshid

AU - Burnett, Lisa C.

AU - Rosenbaum, Michael

AU - Zhang, Yiying

AU - Ding, Li

AU - Moresco, James J.

AU - Diedrich, Jolene K.

AU - Yates, John R.

AU - Tillman, Heather S.

AU - Leibel, Rudolph L.

AU - Talkowski, Michael E.

AU - Billadeau, Daniel D.

AU - Reiter, Lawrence T.

AU - Potts, Patrick Ryan

PY - 2020/9/3

Y1 - 2020/9/3

N2 - Prader-Willi syndrome (PWS) is a developmental disorder caused by loss of maternally imprinted genes on 15q11-q13, including melanoma antigen gene family member L2 (MAGEL2). The clinical phenotypes of PWS suggest impaired hypothalamic neuroendocrine function; however, the exact cellular defects are unknown. Here, we report deficits in secretory granule (SG) abundance and bioactive neuropeptide production upon loss of MAGEL2 in humans and mice. Unbiased proteomic analysis of Magel2pΔ/m+ mice revealed a reduction in components of SG in the hypothalamus that was confirmed in 2 PWS patient-derived neuronal cell models. Mechanistically, we show that proper endosomal trafficking by the MAGEL2-regulated WASH complex is required to prevent aberrant lysosomal degradation of SG proteins and reduction of mature SG abundance. Importantly, loss of MAGEL2 in mice, NGN2-induced neurons, and human patients led to reduced neuropeptide production. Thus, MAGEL2 plays an important role in hypothalamic neuroendocrine function, and cellular defects in this pathway may contribute to PWS disease etiology. Moreover, these findings suggest unanticipated approaches for therapeutic intervention.

AB - Prader-Willi syndrome (PWS) is a developmental disorder caused by loss of maternally imprinted genes on 15q11-q13, including melanoma antigen gene family member L2 (MAGEL2). The clinical phenotypes of PWS suggest impaired hypothalamic neuroendocrine function; however, the exact cellular defects are unknown. Here, we report deficits in secretory granule (SG) abundance and bioactive neuropeptide production upon loss of MAGEL2 in humans and mice. Unbiased proteomic analysis of Magel2pΔ/m+ mice revealed a reduction in components of SG in the hypothalamus that was confirmed in 2 PWS patient-derived neuronal cell models. Mechanistically, we show that proper endosomal trafficking by the MAGEL2-regulated WASH complex is required to prevent aberrant lysosomal degradation of SG proteins and reduction of mature SG abundance. Importantly, loss of MAGEL2 in mice, NGN2-induced neurons, and human patients led to reduced neuropeptide production. Thus, MAGEL2 plays an important role in hypothalamic neuroendocrine function, and cellular defects in this pathway may contribute to PWS disease etiology. Moreover, these findings suggest unanticipated approaches for therapeutic intervention.

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Loss of MAGEL2 in prader-willi syndrome leads to decreased secretory granule and neuropeptide production

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