Prader-Willi syndrome (PWS) is a neurodevelopmental disorder with a known genetic etiology, but a complex epigenetic basis.  PWS is an imprinted disorder, meaning that the genes implicated in PWS are expressed only on the paternal but not the maternal chromosome 15q11-13. At the heart of the minimally deleted region in PWS are several processed subunits of a long noncoding RNA transcript. While most of the prior attention in PWS research has been on the processed snoRNAs that localize to nucleoli of mature neuronal nuclei, the LaSalle lab has recently characterized a functional relevance to the spliced “host gene” for the snoRNAs, 116HG (Powell el at, HMG, 2013).  This study demonstrated that 116HG forms a large nuclear RNA “cloud” during sleep in postnatal neuronal nuclei. The 116HG RNA cloud remains tethered to its site of transcription and co-purifies with active metabolic genes, including mammalian target of rapamycin (Mtor).  In the Snord116 deletion mouse model of PWS, Mtor transcript and protein levels were elevated during light (sleep, Zt+6) but not dark (wake, Zt+16) phases.  The mTOR imbalance corresponded to a metabolic phenotype of increased lipid oxidation and reduced respiratory exchange ratio (RER) during light hours.  In order to translate these novel findings into a potential therapy for PWS, the goal of this proposal is to treat the metabolic and behavioral phenotypes of Snord116del mice with early light hour administrations of rapamycin, beginning at weaning and continuing for 7 weeks.  Since rapamycin is an FDA-approved and widely used drug for cancer and transplantation, as well as in clinical trials for children with tuberous sclerosis, the repurposing of this drug for PWS clinical trials could be a possible outcome of this proposed study.


Rapamycin treatment corrected the mTOR pathway deficits, but reduced body weights of both WT and PWS mice, compounding the lower weight phenotype of Snord116+/- mice rather than correcting it.

Funded Year:


Awarded to:

Janine LaSalle, PhD




University of California Davis