The 5-HT2CR: Mining a new experimental approach to therapeutics for Prader-Willi syndrome

Prader-Willi Syndrome (PWS) is a complex genetic disorder in which several genes are missing or not functional. PWS is characterized by initial loss of muscle tone and failure to thrive neonatally; children with PWS develop behavioral and cognitive problems, reproductive defects, and excessive overeating. A major medical concern is the morbid obesity that results from incessant food-seeking and an inability to feel full. The chromosomal defect in PWS patients deletes a gene sequence involved in regulating a receptor found in the brain, the serotonin 5-HT2C receptor (5-HT2CR). Brain serotonin (5-HT) pathways are well-characterized to regulate feeding, satiety, and mood. Drugs that enhance 5-HT function have been shown to reduce weight and severity of illness in obese patients. The 5-HT2CR appears to be an important component for the weight reducing effects of these drugs, as the drugs are ineffective when the 5-HT2CR is blocked, or in mice that lack the 5-HT2CR. Thus, the brain 5-HT2CR plays a critical role in the control of food intake and satiety, however its potential as a therapeutic target for obesity associated with PWS has not been investigated. We hypothesize that selective and sustained activation of 5-HT2CR may therapeutically enhance the health and lifestyles of PWS patients. A specific part of the 5-HT2CR  molecule makes a physical interaction with a protein known as PTEN. This association of PTEN with 5-HT2CR limits downstream effects caused by stimulation of 5-HT2CR. Thus, a selective inhibitor of the 5-HT2CR:PTEN interaction would enhance 5-HT2CR signaling. In the proposed studies, we will characterize the 5-HT2CR:PTEN interaction by measuring intracellular responses in cultured cells containing 5-HT receptors in the presence or absence of PTEN. We will design, synthesize and evaluate novel peptides that inhibit interaction between the 5-HT2CR and PTEN. These studies will enable us to ultimately design small molecules to enhance 5-HT2CR function and identify their efficacy in preclinical models as potential therapeutics for treatment of PWS.