Dr. Atasoy and his team have recently discovered that the protein Magel2 is important in allowing oxytocin neurons in the brain to communicate normally. These neurons are involved in social behavior, cognition and infant feeding. This funded project will study a mouse model of PWS that is lacking Magel2, to understand how loss of Magel2 impacts communication of these neurons, and how brain circuits change when Magel2 is missing.
Watch the full webinar describing all 9 research projects funded in this grant cycle here.
PWS is caused by the loss of function of a set of genes. One of these genes, MAGEL2, produces a protein that is important for the normal development of the brain, muscles and the endocrine system. Loss of function of MAGEL2 alone, or having an incomplete MAGEL2 protein, causes a disorder that is related to PWS, called Schaaf-Yang syndrome (SYS). Researchers have only studied the function of half of the MAGEL2 protein, while the function of the other half of the protein remains unknown. Proteins can have many activities in cells: they can form structures, they can transport other proteins around the cell, they can generate energy for the cell to use, or they can have many other activities that keep a cell healthy. Some proteins are more active in only some organs. For example, MAGEL2 is most active in the brain, in muscle, cartilage and bone, and in the adrenal glands. MAGEL2 is especially important for maintaining normal sleep and wake cycles, for muscle strength and endurance, and for hunger responses in parts of the brain that control appetite and body weight.
We will investigate the function of the MAGEL2 protein, to better understand the consequences of loss of function of MAGEL2. We will determine which proteins MAGEL2 interacts with in the cell: the function of MAGEL2 protein is likely related to the function of proteins that it interacts with. We recently discovered that the N-terminus of MAGEL2 protein interacts with a set of proteins important for the stability of mRNAs. mRNAs tell the cell what proteins to make. Some mRNAs give their instructions for protein production at the synapses of neurons, where information is sent to other neurons and to muscles. We think that the N-terminal half of MAGEL2 binds to complexes that contain mRNAs, while the C-terminal half controls the stability of those complexes through a known function of MAGEL2 in protein ubiquitination. This activity is entirely missing in PWS. In SYS, the partial MAGEL2 protein can bind to mRNA containing complexes but not degrade them, which may be why SYS can be more severe than PWS. We already found that MAGEL2 interacts with proteins important for day-night rhythms, and with proteins that are missing in children with other genetic forms of developmental disability.
We will determine whether cells that have no MAGEL2 (like in PWS) or only have the first half of MAGEL2 and not the second half (as is often the case in SYS) have defects in the pathways that we uncover through the protein-protein interaction analysis. Pharmacological therapies that are being tested in PWS have beneficial effects on mice lacking the MAGEL2 gene, improving their muscle and bone mass, lowering their fat mass, and reducing their appetites. We anticipate that the MAGEL2 pathways that we uncover through protein-protein analysis will form the basis for the choice of pharmacological therapies (either already approved therapies or novel therapies) that could be beneficial in PWS and SYS.
Deniz Atasoy, Ph.D.
University of Iowa
Deniz Atasoy, Ph.D.