@article{70149e55c6bb4643bfc142ce00064c11,
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 = "Funding Information: We thank the subjects with PWS and their families for donating materials to make these studies possible. We thank members of the Potts lab for helpful discussions and critical reading of the manuscript. We would like to also acknowledge the St. Jude Children's Research Hospital Vector Development & Production Core, Cell and Tissue Imaging Center, and Animal Resources Center. This work was supported by Foundation of Prader-Willi Research grant 557417 (PRP and LTR), NIH/National Institute of General Medical Sciences (NIH/NIGMS) 1R01GM111332 (PRP), NIH/National Institute of Diabetes and Digestive and Kidney Diseases (NIH/NIDDK) 5R01DK052431-24 (RLL), NIH/NIGMS P41GM103533 (JRY), and NIH/NIDDK 1R01DK107733 (DDB). HC was supported by a postdoctoral fellowship from the St. Jude Children's Research Hospital. LD was supported by a fellowship grant from the Eagles 5th District Cancer Telethon Funds for Cancer Research and the Center for Biomedical Discovery. Funding Information: We thank the subjects with PWS and their families for donating materials to make these studies possible. We thank members of the Potts lab for helpful discussions and critical reading of the manuscript. We would like to also acknowledge the St. Jude Children{\textquoteright}s Research Hospital Vector Development & Production Core, Cell and Tissue Imaging Center, and Animal Resources Center. This work was supported by Foundation of Prader-Willi Research grant 557417 (PRP and LTR), NIH/National Institute of General Medical Sciences (NIH/NIGMS) 1R01GM111332 (PRP), NIH/National Institute of Diabetes and Digestive and Kidney Diseases (NIH/NID-DK) 5R01DK052431-24 (RLL), NIH/NIGMS P41GM103533 (JRY), and NIH/NIDDK 1R01DK107733 (DDB). HC was supported by a postdoctoral fellowship from the St. Jude Children{\textquoteright}s Research Hospital. LD was supported by a fellowship grant from the Eagles 5th District Cancer Telethon Funds for Cancer Research and the Center for Biomedical Discovery. 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)",
volume = "5",
journal = "JCI Insight",
issn = "2379-3708",
publisher = "The American Society for Clinical Investigation",
number = "17",
}