The Foundation for Prader-Willi Research announces our second round of Research Awards in 2019 totaling $708,577. FPWR is dedicated to supporting research that advances the understanding and treatment of Prader-Willi syndrome (PWS) and to that end, has awarded over $13,000,000 to research since 2003.On a recent webinar, Dr. Theresa Strong reviewed each of the 9 funded grants, sharing why we're excited about them and what their potential long term contribution could be. You can watch the full 60-minute webinar here or use the links below to watch short 2-minute segments on each specific project.
FPWR PWS Research Grant Recipients, Fall 2019
Cellular role of MAGEL2 in Prader-Willi and Schaaf-Yang syndromes – (year 2) Rachel Wevrick, PhD, University of Alberta ($108,000) Wevrick’s lab has been investigating the function of the PWS-region gene, MAGEL2, to better understand the consequences of loss of that gene. They have found that MAGEL2 interacts with proteins important in stabilizing RNAs and in regulating circadian rhythm. In year 2 of funding, they will validate the MAGEL2 protein interactions identified, and determine the downstream effects of MAGEL2 function, setting the stage for evaluating therapeutic interventions to compensate for MAGEL2 loss.
Role of the PWS gene Magel2 in the developing hypothalamus Malcolm Low, PhD University of Michigan ($105,300). Low is an expert in the neurobiology of appetite. His group has discovered that Magel2 is active in a set of neurons that regulates appetite. Here, they will apply a newly developed ‘single cell sequencing’ approach to examine the development of these brain circuits in a mouse model of PWS, providing insight into how alterations in these circuits leads to abnormal appetite in PWS. [Funding provided by the Dave & Nancy O’Neill Charitable Fund]
Evaluating endosomal recycling pathways in primary neurons from PWS individuals (year 2) Ryan Potts, PhD. St. Jude ($108,000). Dr. Potts has used cells from PWS ‘baby teeth’ to identify changes in vesicle recycling in cells from individuals with PWS. They have evidence of developmental changes in cells from individuals with PWS compared to typical individuals. Here they will further characterize and quantify these changes, to better understand the cellular basis of PWS and potentially develop a platform to screen drugs to restore normal function.
Investigation of rapamycin as a therapeutic option in a mouse model of Schaaf-Yang syndrome (SYS) Christian Schaaf, MD PhD, University Hospital Heidelberg ($108,000). In a mouse model of PWS and SYS, and in neurons generated from skin fibroblasts of individuals with SYS, Dr. Schaaf’s has discovered a marked upregulation of the ‘mTOR’ pathway, a pathway that is important for many cellular processes. Importantly, there are known drugs that can reduce the activity of the pathway. Schaaf will investigate whether one of these drugs, rapamycin, has a positive impact on cellular and mouse models of SYS.
Investigating the cause of mental illness in PWS using Magnetic Resonance Spectroscopy (MRS). Tony Holland MD, Cambridge University ($92,077). Holland is a psychiatrist with a long standing interest in understanding why individuals with PWS are susceptible to mental illness. Here he will use a brain imaging technique to look at levels of the neurotransmitter, GABA. He hypothesizes that alterations in GABA levels might be the basis of behavioral problems and psychosis in PWS. This study will also examine brain structure, cognition and genetic subtypes as determinants of risk for mental illness in PWS, with the goal of developing strategies to prevent psychiatric problems.
Role of MAGEL2 in excitatory synapse function Deniz Atasoy, PhD University of Iowa ($64,800). Atasoy’s group has recently discovered that the Magel2 protein is required for normal communication between oxytocin neurons, which are known to be involved in social behavior and infant feeding. This project will use a PWS mouse model to examine the role of Magel2 in neuronal communication and the normal function of brain circuits.
Role of central amygdala anorexia neural circuits in Prader-Willi Syndrome Haijing Cai, PhD, University of Arizona ($64,800) This proposal will investigate the defects in satiety signaling in a mouse model of PWS. Cai hypothesizes that a particular set of neurons in the amygdala do not convert satiety signals properly, and this is the basis for impaired appetite suppression in PWS. They will use cutting edge methods to investigate this hypothesis.
Allele-specific DNA replication timing of the Prader-Willi locus and its influence on neuronal development Amon Koren, PhD, Cornell University ($54,000). Using state-of-the-art technologies in human genomics and human stem cells, Dr. Koren has discovered that loss of paternal PWS genes results in defective DNA replication, which may explain the how the characteristics of PWS arise. Here, they will measure DNA replication, cell division, and neuronal development in cells from healthy subjects and PWS patients, to understand if changes in DNA replication leads to developmental alterations that underlie the PWS characteristics.
Neuronal mechanisms of developmental cognitive impairment in the Snord116del mouse model for Prader-Willi Syndrome Timothy Wells, PhD, Cardiff University ($3,600). In a summer project, a student in Dr. Wells’ laboratory will explore the basis of impaired cognition in a mouse model of PWS. The developmental differences in neurons, including dendrite size, shape, and branching, will be characterized and compared to the neuronal development in wild type mice.