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 Magel2 p Δ /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.

Hypothalamic neuropeptides and neurocircuitries in Prader Willi syndrome

“…42,43 At the cellular level, its loss results in a decreased neuropeptide production and secretory capacity. 12 Moreover, MAGEL2 null new born mice also display poor sucking as PWS infants. 44…”

“…A recent report has demonstrated that neurons from PWS patients have decreased secretory granules and neuropeptides production. However, the authors attribute this defect to the MAGEL2 gene 12 . Since PWS T1 have more severe phenotypic traits it is possible that the additional loss of NIPA1 hampers the neuroendocrine maturation and secretion 12 …”

A Comprehensive Review of Genetically Engineered Mouse Models for Prader-Willi Syndrome Research

“…MAGEL2 (Melanoma Antigen-subfamily like 2) is another paternally imprinted intronless gene, within the PWS locus ( Figure 1 ) [ 64 , 72 , 105 ]. The human gene encodes a protein of 529-amino acids (525 amino acids in mouse) that displays about 51% sequence similarity to NECDIN, and functions as an E3 ubiquitin ligase enhancer involved in retromer endosomal protein trafficking [ 106 , 107 , 108 ].…”

“…In addition, the lack of Magel2 in KO mice was accompanied by reduced levels of several neuropeptides, i.e., oxytocin and orexins. Furthermore, the expression of regulatory proteins that participate in processing and exocytosis of neuropeptides via secretory granules was compromised [ 53 , 71 , 72 ]. Magel2 null mice also revealed higher levels of mTOR and its downstream signaling targets in the hypothalamus [ 68 ].…”

The Effects of Oxytocin on Appetite Regulation, Food Intake and Metabolism in Humans

“…Schaaf–Yang syndrome is a rare neurodevelopmental disorder that has a strong clinical overlap with PWS [ 249 ]. It is caused by mutations in the MAGEL2 gene, which is located in the PWS critical region on chromosome 15q11.2-q13 [ 250 ] and has a pivotal role in hypothalamic neuroendocrine function [ 251 ]. Rodents with MAGEL2 mutations provide an animal model through which PWS can be investigated.…”