Elucidating Phenotypic Differences between PWS and SYS: Exploring MAGEL2 Fate in Human Neurons

Funding Summary

Dr. Laugsch's group will examine the normal function of the MAGEL2 protein compared to MAGEL2 harboring SYS mutations, analyzing neuronal growth and function in the laboratory dish.

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

Lay Abstract

Our mission is to understand the role of the MAGEL2 gene upon neuronal development in health and disease including PWS and SYS. Both disorders result in common and distinct symptoms, with MAGEL2 being absent in PWS and mutated in SYS. To deepen our knowledge of MAGEL2 function, we utilize human cell models (hiPSC) and gene scissors (CRISPR/Cas9). We differentiate these hiPSC into neurons to recapitulate early human development and elucidate the pathophysiology of SYS and PWS by comparing cells with normal and aberrant MAGEL2. Utilizing state-of-the-art techniques from various disciplines (cell biology, epigenomics, bioinformatics, network biology), we found that the structure of neurons is altered in SYS and PWS cells. To elucidate the mechanism, by which aberrant MAGEL2 leads to this phenotype, we will investigate the place where MAGEL2 is located in the neurons. This is important because the function of proteins often depends on their localization, which may differ between neurons and cancer cells. In addition, we will identify proteins that work together with normal and aberrant MAGEL2 (interaction partners), which may also differ between the cell types. Determining the localization and direct interaction partners will give essential information about the function of MAGEL2 in human neurons, which has so far mainly been determined in cancer cells. Our novel approach (hiPSC with marked healthy and mutated MAGEL2, whose presence can be controlled) to restore the MAGEL2 presence in SYS and PWS neurons, will help to explore if and to what extent the aberrant structure of neurons can be repaired. The knowledge gained from this study will deepen our understanding of SYS and PWS pathology, providing a novel and multifaceted picture of MAGEL2 function. In addition, we will use these cells to explore the role of MAGEL2 in a process that can be compared to the drops of oil and vinegar that separate before mixing the salad dressing. We will uncover whether MAGEL2 is involved in such process and measure the nature and size of these drops. These data could revolutionize the understanding of MAGEL2 function in the brain and open up entirely new therapeutic avenues for SYS and PWS that may significantly improve the lives of people affected by these disorders. 

Overall, the innovative methodology of our study combines a range of unique CRISPR/Cas9-engineered hiPSC lines, their neuronal differentiation and multi-omics studies. It enables powerful modeling of SYS and PWS that offers unique insight into the role of MAGEL2 in health and disease. The funding we request will allow us to generate data and establish experimental strategies that will facilitate future funding and international projects. Therefore, our cell lines generated for and in this study will be available in the FPWR hiPSC Biobank, and our bioinformatical data will be accessible to other researchers.