A functional link between a cluster of non-coding RNAs implicated in Prader-Willi Syndrome (PWS) and dysregulation of energy homeostasis has been demonstrated by research from the group of Anthony Coll, Steve O’Rahilly and Giles Yeo, which was recently published in The Journal of Clinical Investigation. The study created a new mouse model of the disease, successfully inducing hyperphagia. A refined version of the model could be used to test potential therapies for PWS patients.
Hyperphagia and obesity are responsible for most of the morbidity and mortality associated with PWS yet these symptoms remain poorly understood and without effective pharmacologic therapies. While humans with a SNORD116 deletion become hyperphagic and obese, mice with a genetic Snord116 deletion are small, similar to the early failure to thrive in human PWS patients, but they do not become obese. The authors hypothesised that deleting Snord116 in the hypothalamus of adult mice would bypass the early growth phenotype, and possibly uncover a metabolic or food intake phenotype.
In the current study, mice with an adult-onset hypothalamic deletion of Snord116 were generated using stereotaxic injections of AAV driven Cre-recombinase in to the hypothalami of mice with LoxP sites flanking Snord116, which then resulted in a temporally and spatially specific deletion of Snord116. These mice were demonstrably hyperphagic, and a percentage also became obese. This highlighted the hypothalamic role of Snord116 in the hyperphagia of PWS. Interestingly, no changes in hypothalamic melanocortin or prohomone processing gene expression were seen when Snord116 was deleted, suggesting that these energy homeostasis pathways remained intact in the new model. Ultimately, the authors plan to further refine this preclinical model for PWS, which could be used to test interventions for PWS hyperphagia.