Dr. Kurrasch is studying whether inflammation in the brain, mediated by special immune cells called microglia, might contribute to hyperphagia and obesity in PWS. Using a mouse model of PWS, she will examine microglia activity and explore whether eliminating microglia improves energy regulation.
Funding provided by FPWR – Canada.
Theresa Strong, Director of Research Programs, shares details on this project in this short video clip.
Watch the full webinar describing the 11 research projects funded in this grant cycle here.
In individuals with PWS, dysregulation of appetite signaling across hypothalamic circuits is largely responsible for urges to eat and concomitant obesity. Despite advancements in our understanding of hypothalamic changes associated with PWS, the underlying mechanisms for the development of obesity are still emerging. Here, we hypothesize that undiagnosed neuroinflammation in individuals with PWS adversely influences hypothalamic signaling centers, promoting hyperphagia and obesity.
Indeed, adults with PWS display elevated inflammatory markers, consistent with low-grade systemic inflammation that may be a genetic feature of PWS. Perhaps even more tellingly, hundreds of genes involved in inflammatory processes are upregulated in the hypothalamus of postmortem PWS brains, directly demonstrating hypothalamic neuroinflammation in PWS individuals. Using Magel2+/-P mice as a model for PWS, we demonstrated that the neuroimmune cell, microglia, were increased in the hypothalamus of these animals and furthermore, were highly reactive when challenged with a high fat diet. Together, these data point to an unappreciated role for activated microglia in the PWS hypothalamus.
Here, we propose to study neuroinflammation in two mice models of PWS – Magel2+/-P and Snord116-AAV-Cre. We will examine the adult hypothalamus for changes in microglia number and activation state. We will also test whether the hypothalamus in these models secrete molecules associated with neuroinflammation. Finally, we will ask if the elimination of microglia in two mice PWS models decreases body fat and/or food intake.
Why this research is important. If pharmaceutical agents could help normalize aberrantly functioning hypothalamic feeding circuits, then the lives of PWS individuals and their families would improve. Here, we propose a new and currently unappreciated druggable target that could potentially make inroads on this persistent eating phenotype and attendant obesity.
Logical next steps. In this proposal, we use two mouse models of PWS to ask if microglia are an additional layer of dysfunction in the PWS hypothalamus, and whether the elimination of microglia improves energy regulation. In Year 2 we will explore the underlying mechanism linking microglia activation to dysregulation of hypothalamic neurons.
How this project lays the foundation for therapeutic development. On clinicaltrials.gov, there are over 30 clinical trials exploring the contributions of microglia to various central nervous system (CNS) diseases, ranging from Alzheimer’s to schizophrenia to ALS. Thus, there is considerable interest by the pharmaceutical industry to target microglia to relieve CNS disease symptoms, which can be directed to patients with PWS if appropriate. At the same time, our work suggests that the ketogenic diet, which decreases neuroinflammation, might also be efficacious in individuals with PWS.
Research Outcomes: Public Summary
Collectively, our findings support the idea that neuroinflammation might play an underappreciated role in the etiology of Prader-Willi. Using the Magel2-null mice as a model system, we demonstrate changes in microglial activation states and numbers in null brains, especially within hypothalamic regions critical for proper energy balance. We also uncovered a population of microglia that are lost in Magel2-null animals particularly during the juvenile to adult transition time point, suggesting that these microglia might be required for shaping these energy balance circuits specifically at this developmental stage. Our long-term goal is to further study the influence of microglia in the PWS brain to assess whether microglia could be an eventual druggable target for the treatment of the hyperphagia phenotype that presents in childhood.
Deborah Kurrasch, PhD.
University of Calgary
Deborah Kurrasch, PhD.