Investigation of the Role of Fkbp5 to Induce PWS Phenotypes in a Magel2-null Mouse Model

Funding Summary

With previous FPWR funding, Dr. Yu used advanced, single-cell sequencing to characterize changes in hypothalamic cells in a PWS mouse model and identified activation of a gene important in stress response and energy metabolism, Fkbp5. Here she will test whether inhibiting Fkbp5 rescues deficits in a PWS mouse model.

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

Lay Abstract

Magel2 is one of a handful of genes located next to each other at a specific location on human chromosome 15. Its loss of function is partially responsible for the development of Prader-Willi syndrome (PWS). Many, but not all, of the characteristic clinical features of PWS including hormonal, reproductive, metabolic and behavioral problems are replicated in a strain of Magel2-null mice that cannot produce the MAGEL2 protein. Although the molecular and cellular functions of MAGEL2 have been extensively studied, it still remains elusive how loss of function of MAGEL2 actually causes PWS-like features. Many studies have concluded that a part of the brain called the hypothalamus is particularly important. In our previously funded project, we used a recently developed technique called single-cell RNA sequencing, which decodes genomic information from individual cells, to identify additional genes with altered expression levels in the hypothalamic cells of Magel2–null mice. One of these genes called Fkbp5 was significantly up-regulated compared to control mice of both sexes. Previous studies by other investigators have shown that Fkbp5 was also increased in hypothalamic tissue from deceased PWS patients and from the hypothalamus of another mouse strain that lacks expression of a second gene called Snord116, which is located close to Magel2 on chromosome 15. Furthermore, elevated levels of FKBP51 (the protein product of Fkbp5) increase behavioral and hormonal responses to stress and alter the normal regulation of body weight, fat mass and blood sugar in mice fed a high fat diet. Our recent study injecting a drug called SAFit2, which specifically blocks the function of FKBP51, to Magel2-null and control mice showed that Magel2-null mice had reduced food intake compared to their control siblings. Interestingly, an increased level of Fkbp5 was found in the paraventricular hypothalamus (a specific brain region that mainly regulates feeding behavior and stress responses) of Magel2-null mice. Based on these new findings, we hypothesize that the upregulation of Fkbp5 in mice lacking Magel2 is necessary for development and persistence of their PWS-like phenotype. We will test this hypothesis using two sets of independent experiments. Since Magel2-null mice have abnormal response to stress, in the first experiment, we will block FKBP51 function in brain through the direct injection of SAFit2 into brain and evaluate whether it will correct the disturbed stress response in Magel2-null mice. Corticosterone (the rodent version of cortisol) levels will be measured under different stress conditions. Since we observed that SAFit2 reduced food intake in Magel2-null mice, in the second experiment, we will inject SAFit2 in the brain, monitor and compare their feeding behavior and energy expenditure to the normal control mice. FKBP51 is an established therapeutic target for several neurobehavioral disorders in humans and can be chemically modified to fine tune its activity. Therefore, our predicted results may provide valuable preclinical evidence that inhibition of FKBP51 signaling is a potential new treatment for children with PWS.

Research Outcomes: Public Summary

This study aimed to assess the potential of pharmacological inhibition of FKBP51 signaling in mitigating the impaired behavioral and metabolic phenotypes observed in Magel2-null mice. The selective FKBP51 antagonist, SAFit2, was administered chronically to both Magel2-wt and Magel2-null mice for subsequent behavioral and metabolic evaluations. Consistent with existing literature, Magel2-null mice exhibited a significant increase in fat mass, reduced food intake during the dark cycle, delayed counterregulatory response to hypoglycemia, prolonged time spent in the open arm, and increased frequency of entry into the open arm in the elevated plus maze test, along with elevated corticosterone levels in the morning and comparable levels under stress and insulin stimulation.
SAFit2 treatment in Magel2-null mice induced substantial alterations in these reported phenotypes. Specifically, it significantly ameliorated the delayed counterregulatory response to hypoglycemia in Magel2-null mice, reduced the frequency of entry into and the duration spent in the open arm in the elevated plus maze test, and markedly decreased the duration of time spent in the center zone in the open field assay. SAFit2 also influenced the response of Magel2-null mice in the dexamethasone - corticotropin-releasing hormone combined (Dex-Crh) test. While SAFit2-treated Magel2-wt mice exhibited reduced circulating corticosterone levels after Crh stimulation, Magel2-null mice with SAFit2 treatment displayed similar levels of plasma corticosterone. Despite the treatment, disruptions in the circadian rhythm of circulating corticosterone levels were observed in Magel2-null mice, as evidenced by comparable levels in both morning and evening measurements.
In conclusion, our study suggests that antagonizing FKBP51 signaling could partially reverse the abnormal phenotypes exhibited in Magel2-null mice.

Funded Year:


Awarded to:

Hui Yu, Ph.D.




University of Michigan


Hui Yu, PhD

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