Cellular and molecular basis for obesity in PWS

Funding Summary

In this project we propose to use a newly-developed powerful tool to identify the specific nerve cells and genes that cause the hyperphagia in individuals with PWS and then screen for drugs to correct their functions and treat the obesity associated with PWS using the MAGEL2-null mouse model. We hypothesize that those cells showing significant changes in gene expression in mice lacking MAGEL2 contribute to the hyperphagia and obesity in PWS. Once the causal role of candidate cells and genes has been confirmed, we will identify drug targets that would be expected to inhibit cells that drive appetite or activate cells that reduce appetite. These studies will lay a solid foundation of our understanding of the mechanisms underlying hyperphagia and obesity in PWS, and more importantly, provide a rational (i.e; non-empiric) means for identifying drugs that engage those drug targets to treat the disorder.

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

Lay Abstract

Individuals with Prader-Willi Syndrome (PWS) typically show uncontrollable overeating (hyperphagia) which is one of the most distressing symptoms and to date there are no approved treatments for this condition. PWS results from deletion of a part of chromosome 15 which alters the expression of several genes that normally regulate the function of a brain region known as hypothalamus. This region is a master regulator of food intake and energy expenditure, and hyperphagia and obesity usually result from the dysfunction of hypothalamus. Indeed, an impairment of hypothalamus function has been reported in individuals with PWS. The hypothalamus contains a large number of different types of nerve cells each with distinct functions and some cells promote feeding while other suppress appetite. However, the identity of the specific types of nerve cells in the hypothalamus that are affected and how they are changed in patients with PWS are not known, which makes it difficult to develop appropriate therapeutic strategies. In this application we propose to use a newly-developed powerful tool to identify the specific nerve cells and genes that cause the hyperphagia in individuals with PWS and then screen for drugs to correct their functions and treat the obesity associated with PWS. To do so, we will employ the widely-used PWS mouse model, i.e. MAGEL2-null mice. Mice with a mutation in MAGEL2 gene show many of the same features of PWS patients including hyperphagia. Thus we can use the information derived from studies of these mice to identify drug targets that potentially contribute to PWS in human. We will first systematically and comprehensively characterize cell-specific gene expression changes in hypothalamic neurons of MAGEL2-defective mice by using a powerful new technique known as multiplexing single nuclear RNA sequencing (snRNA-seq). This method enables one to identify all of the expressed genes in individual cells. We will apply this technique to study the genes that are expressed in many thousands of individual hypothalamic nerve cells from normal mice and MAGEL2-mutant mice. We hypothesize that those cells showing significant changes in gene expression in mice lacking MAGEL2 contribute to the hyperphagia and obesity in PWS. After characterizing gene expression profiles, we will use powerful computational tools to identify key cells and genes that are dysregulated in mice lacking MAGEL2 and then use genetic tools and feeding-related behavioral tasks to test whether these cells and the genes they express cause hyperphagia and obesity. Once the causal role of candidate cells and genes has been confirmed, we will further analyze the genes expressed in the cells that contribute to the obesity to identify drug targets. Specifically, we will identify drug targets that would be expected to inhibit cells that drive appetite or activate cells that reduce appetite. These studies will lay a solid foundation of our understanding of the mechanisms underlying hyperphagia and obesity in PWS, and more importantly, provide a rational (i.e; non-empiric) means for identifying drugs that engage those drug targets to treat the disorder.