MAGEL2 role in adaptive stress response: New insights into MAGEL2 function and pathogenesis of PWS

Funding Summary

Dr. Fon Tacer has been investigating the function of the MAGEL2 protein and believes it plays an important role in how cells adapt to stress. In this study she will explore how cellular stress responses are altered when MAGEL2 is lost.

Dr. Theresa Strong, Director of Research Programs, shares details on this project in this short video clip. 

Lay Abstract

With the proposed project we aim to get the first insight into the role of PWS-associated gene MAGEL2 in the regulation of the hypothalamus-pituitary-adrenal axis (HPA) in animals under stress. The HPA axis is the master regulator of our body’s stress response that allows for efficient adaptation to acute and chronic changes in the environment, important for normal development and health. Several symptoms, including characteristic behavior, hyperphagia, and autism spectrum disorder, suggest that the adaptation is severely compromised in PWS/SYS patients. In an ever-changing environment, stress response and adaptation to various homeostatic challenges were evolutionary critical for survival. Multiple and overlapping mechanisms evolved to deal with both acute and prolonged threats. Melanoma antigen (MAGE) protein family expanded very recently in evolutionary history from one gene in ancestral eukaryotes to more than forty genes in our genomes. Recent discoveries that several MAGE protein family members which are uniquely expressed in male germs cells evolved because they protect germline and fertility under stressful conditions and provided evolutionary advantage under suboptimal conditions, provided a new view of the physiological role of these proteins. In this proposal, we aim to investigate whether MAGEL2, too, provides benefit under stress and faster adaptation to homeostatic challenges. MAGEL2 is a gene frequently deleted or mutated in individuals affected with PWS and SYS. Furthermore, mice lacking MAGEL2 display symptoms similar to those seen in PWS/SYS children. We have previously shown that MAGE-L2 functions to prevent aberrant degradation of specific proteins that normally reside in the plasma membrane or are secreted by the hypothalamus, including several neuropeptides. Here, we will investigate the role of MAGEL2 in the hypothalamus, pituitary, and adrenal, where MAGEL2 is expressed, in animals that encounter stress. We will perform analysis by single-cell and in situ gene expression analysis, determining MAGEL2 binding partners under stress, and investigating MAGEL2 role in specialized translation, one of the major cellular mechanisms to cope with stress in the central nervous system. We expect that the results of the proposed studies will provide completely novel insight into MAGEL2 molecular function in the hope of discovering better therapeutic avenues to help children and adults with PWS and SYS.

Research Outcomes: Public Summary

In this project, we aimed to take an unbiased approach to investigate the molecular function of Magel2 in a physiological context. To date, most molecular and cellular insights have come from in vitro studies using cell lines such as HEK293, which do not express Magel2. In contrast, important physiological insights have been gained from two existing mouse models, including our recent discovery of Magel2’s role in endocrine hormone secretion. However, key questions remain regarding how MAGEL2 regulates the secretory pathway, its molecular partners, and the cellular pathways it controls in tissues where it is normally expressed—particularly in the hypothalamus during physiological stress, such as fasting.
These were the core questions we set out to address through this multi-PI project, which brought together complementary expertise from three collaborative laboratories at TTU and TTUHSC. We designed experiments to study stress responses to food deprivation and, in parallel, optimized key molecular techniques for use in mouse tissues, including MAGEL2 immunoprecipitation, single-nucleus RNA sequencing (snRNA-seq), and polysome profiling.
The findings from this work establish a strong foundation for discovering novel—and potentially previously unrecognized—functions of Magel2, particularly in the context of fasting and refeeding, which are central to clinical concerns in PWS and related disorders involving dysregulated hunger and satiety. This research is especially timely in light of the recent FDA approval of the first treatment for hyperphagia in PWS.
Our results may help identify biomarkers to assess treatment efficacy and distinguish responders from non-responders. We also performed proteomic analyses of plasma and hypothalamic tissues, providing insights into potential serum biomarkers and additional MAGEL2 functions. Finally, we established polysome profiling protocols for both the hypothalamus and pituitary, and performed snRNA-seq on hypothalamic tissue from fed and fasted male mice.
These optimized methods will be instrumental in validating and extending our findings—specifically, to determine MAGEL2’s role across distinct hypothalamic cell types, whether and how it regulates protein translation, and to identify its physiologically relevant molecular partners, which we will pursue in the next phase of this work.