Hyperphagia is thought to be a problem of neurons in the hypothalamus, caused by a dysregulation of neurons that signal being full and being hungry. Disruptions in the code for chemical modifications of RNA (called the epitranscriptome) can have detrimental effects on how neurons function. This project will use human hypothalamic hunger neurons created from stem cells with or without the PWS gene, SNORD116, to provide the first glimpse of how loss of SNORD116 might impact the epitranscriptome.
This project was funded in part by FPWR-UK.
Dr. Theresa Strong, Director of Research Programs, shares details on this project in this short video clip.
Hyperphagia continues to be a significant clinical issue for Prader Willi syndrome patients and their families. A full understanding of the molecular mechanism(s) causing the constant hunger and food-seeking behavior may help to develop effective therapies. Many studies have pinpointed the driver of this clinical manifestation to be a dysfunction within the hypothalamus and specifically due to loss of the SNORD116 genomic region on chromosome 15q. The dynamic activity shift between appetite signaling/hunger neurons and satiety-inducing neurons appears to be dysregulated with possible over- or inappropriately sustained activity of the hunger neurons. We hypothesize that this is due to changes to chemical modifications of RNA molecules that enable proper activity induced by fasting and proper “silencing” during fed states. These chemical modifications to RNA, termed the epitranscriptomic code, allows for rapid adjustments by these neurons. Disruption of this code can have detrimental effects on neuronal development, signaling, and response. Epitranscriptomic modifications can have substantial impact on a cell without necessarily changing the quantity of RNA, which makes specific analyses of them important for a full picture. Within the hunger neurons that are considered to be aberrant in PWS patients, we have identified an epitranscriptomic signature that may be driving signaling to maintain energy balance by these key neurons. For this study, we will use human hypothalamic hunger neurons created from stem cells that differ only by presence or absence of SNORD116 to provide the first glimpse of epitranscriptomic control of these specific neurons with respect to SNORD116 absence. We anticipate identifying significant alterations to this signature due to loss of the SNORD116 locus which may help to explain the aberrant activity. We plan to follow up these findings with translational work by assessing whether and how neuronal signatures differ between PWS patients classified as responders or non-responders in ongoing clinical trials, for example. We are poised to recruit patients from the multidisciplinary PWS clinic held monthly at the Children’s Hospital of San Antonio where a majority of the patients are of Mexican American descent. Every patient is genetically diagnosed, and many of these patients participate in pharmaceutical clinical trials, making the clinic a valuable resource for follow-up studies.
Donna Lehman, Ph.D.
University of Texas Health Science Center
Donna Lehman, Ph.D.