Non-coding RNA regulation of neuronal protein translation and appetite control

ABSTRACT Prader-Willi Syndrome (PWS) is a neurodevelopmental disorder with no cure. Individuals with PWS exhibit feeding difficulties and failure-to-thrive in infancy followed by an insatiable appetite and hyperphagia in adulthood. The smallest deletions known to cause PWS involve a paternally expressed cluster of neuron-specific small nucleolar RNAs (snoRNAs), Snord116. The molecular targets and functions of Snord116 are not known. Snord116 is highly expressed in brain regions critical for appetite control, but how Snord116 loss affects the activity of appetite-regulating neurons is also not known. To determine how Snord116 loss alters feeding behavior, it is critical to determine the molecular and cellular functions of Snord116 in appetite-regulating neurons. Most snoRNAs play well conserved roles in ribosome biogenesis and are ubiquitously expressed across tissues. Snord116, uniquely, is preferentially expressed in neurons. Neurons have unique translational demands due to their size and complexity, and neuronal ribosomes have specialized properties to meet those demands. It is not known if Snord116 may contribute to neuron-specific aspects of ribosome biogenesis or protein translation. Therefore, I will investigate the effect of Snord116 loss on neuronal protein translation in parts of the brain known to control appetite. Additionally, I will determine the effect of Snord116 loss on the activity of appetite-regulating neurons and how dysfunction of these neurons may underlie hyperphagia. By delineating the molecular function of a neuron-specific snoRNA, I expect to broadly contribute toward a better understanding of how protein translation is regulated in neurons. Conducting these studies in a relevant population of appetite- regulating neurons also allows us to examine the role of snoRNAs and translation in proper control of feeding circuits in the brain. The insights gained into the molecular basis of appetite control will better inform not only potential therapies for PWS but also obesity, an increasingly prevalent health problem among children.