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Loss of MAGEL2 in Prader-Willi syndrome leads to decreased secretory granule and neuropeptide production
Helen Chen, … , Lawrence T. Reiter, Patrick Ryan Potts
Helen Chen, … , Lawrence T. Reiter, Patrick Ryan Potts
Published September 3, 2020
Citation Information: JCI Insight. 2020;5(17):e138576. https://doi.org/10.1172/jci.insight.138576.
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Research Article Cell biology Neuroscience

Loss of MAGEL2 in Prader-Willi syndrome leads to decreased secretory granule and neuropeptide production

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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.

Authors

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 III, Heather S. Tillman, Rudolph L. Leibel, Michael E. Talkowski, Daniel D. Billadeau, Lawrence T. Reiter, Patrick Ryan Potts

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Figure 6

WASH-mediated protein trafficking prevents lysosomal degradation of SG proteins.

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WASH-mediated protein trafficking prevents lysosomal degradation of SG p...
(A) Transcript levels of Pcsk1, Pcsk2, Chgb, and Cpe in 8-week-old Magel2pΔ/m+ and Magel2+/+ mouse hypothalamuses, n > 3 per genotype. Each data point represents 1 animal, plotted as mean ± SD and analyzed by unpaired, 2-tailed t test, ****P < 0.0001. (B) Transcript levels of PCSK1, PCSK2, CHGB, and CPE between control and PWS iN at 14 days postinduction. Each data point represents 1 induction experiment (n = 3), plotted as mean ± SD and analyzed by 1-way ANOVA. (C) Western blot analysis shows rescued expression of PCSK1, PCSK2, CHGB, and CPE in PWS iN at 14 days postinduction following inhibition of lysosomes by Baf (1 μM, 7 hours) but not inhibition of proteasomes by MG132 (10 μM, 7 hours). DMSO served as vehicle control. GAPDH served as loading control. (D) Quantification of Western blot analysis confirmed reduced expression of Pcsk1 and Pcsk2 in 2-week-old Washc1 conditional knockout (cKO) mouse hypothalamuses, n = 4 per genotype. Gapdh served as loading control. Each data point represents 1 animal, plotted as mean ± SD and analyzed by unpaired, 2-tailed t test, *P < 0.05. (E) Representative images of immunofluorescence staining with CHGB and WASH at both soma and neurite in control iN. Scale bars indicate 10 μm.
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