Investigating the role of Snord116 in ribosome biology

Funding Summary

Through previous work using a new optimized method, Dr. Whipple discovered that Snord116, a driver of PWS, directly interacts with ribosomes, the machinery that produces proteins in the cell in mouse neurons. In this funded project, they will apply their optimized method to human neurons to ask if the interaction between SNORD116 and ribosomes is similar in humans. Then they will use advanced approaches to determine the effect that genetic deletion of Snord116 has on the proteins produced in mouse and human neurons. 

Lay Abstract

This proposal seeks to determine the function of one gene that is deleted in all individuals with PWS. This gene, called Snord116, is thought to be a critical driver of PWS due to the identification of patients carrying a ‘microdeletion’ encompassing the Snord116 gene region. We aim to characterize what Snord116 is doing in neurons– to discover who it is interacting with and what effect it has on the molecular events occurring within neurons. Even though deletion of Snord116 likely results in many changes that eventually cause core symptoms of PWS, there have been major challenges to understand what Snord116 normally does in neurons. This is due, in part, to a lack of experimental tools that can sensitively detect the direct interacting partners of Snord116. We have recently optimized such a method and applied it to mouse neurons. In doing so, we discovered that Snord116 directly interacts with ribosomes, the machinery that produces proteins in the cell. This finding suggests that Snord116 may be required for generating ‘healthy’ ribosomes in neurons, and that the absence of Snord116 may impair the production of proteins in PWS. Here, we will apply our optimized method to cultured human neurons to ask if the interaction between Snord116 and ribosomes is conserved between species. Then we will use advanced approaches to determine the effect that genetic deletion of Snord116 has on the proteins produced in mouse and human neurons. In future work, we will ask how the observed molecular changes impact neural circuits (cellular level) and neurophysiology (organismal level) in PWS models. These foundational experiments seek to characterize the immediate molecular consequences of Snord116 loss, hopefully enabling opportunities to therapeutically correct early events in disease pathology. For example, if protein production is impaired as a direct effect of Snord116 loss, then ribosome targeting therapies could be an avenue of future research.

Our expertise in state-of-the art methods in RNA biology and neurobiology as well as my prior experience in the pharmaceutical industry have uniquely prepared me to tackle outstanding challenges in the PWS field. While the proposed project is heavily rooted in early-stage research, I have personally experienced the rapid progression of basic scientific discovery toward clinical trials for Angelman syndrome and am hopeful that similar success can be achieved for PWS.