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

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

doi:10.1172/jci.insight.138576

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.

Highlights

Prader-Willi syndrome (PWS; OMIM #176270) is a complex neurogenetic disorder that affects 1 in 15,000 children, with 400,000 cases diagnosed globally [1]
Endogenous expression of Magel2 protein is restricted to the hypothalamus and amygdala in the mouse brain
We generated a polyclonal Magel2 antibody against amino acids 970–1284 of the mouse protein corresponding to sequences within the highly conserved MAGE homology domain

Summary

Introduction

Prader-Willi syndrome (PWS; OMIM #176270) is a complex neurogenetic disorder that affects 1 in 15,000 children, with 400,000 cases diagnosed globally [1]. Genetic lesions leading to PWS can be classified into 3 major categories: deletion of paternal 15q11-q13 (65%–75% of cases), maternal uniparental disomy (UPD) (20%–30%), or imprinting defects (1%–3%) [2]. Major clinical features of PWS include neonatal hypotonia and failure to thrive, intellectual and physical disabilities, endocrine dysfunctions, hyperphagia, obesity, maladaptive behaviors, increased risk of type 2 diabetes, and a higher incidence of autism spectrum disorder (ASD) [1, 2]. These broad-spectrum endocrine, neurological, and behavior phenotypes have implicated a number of organ systems, including the neuroendocrine functions of the hypothalamus. Growth hormone replacement therapy is the only FDA-approved treatment for PWS

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Conclusion