The role of the Prader-Willi syndrome obesity protein, MAGEL2 in the proper functioning of circadian rhythm

Abstract

MAGEL2 is one of the five genes inactivated in Prader-Willi Syndrome (PWS), a genetic disorder, manifesting with symptoms of developmental delay and morbid obesity. Magel2 is highly expressed in the suprachiasmatic nucleus, which is the location of the central clock or circadian pacemaker. Magel2 knockout mice exhibit defects in circadian rhythm. I hypothesized that Magel2 plays a role in one of the inter-connecting feedback loops that control circadian rhythm in suprachiasmatic neurons. I determined that Magel2 acts as a repressive protein in the cycle’s feedback loop using a luciferase assay. Magel2 exerts this effect by restricting the movement of Bmal1 into the nucleus. Magel2 levels are then reduced by increasing Per2, associated with increase movement into the nucleus, as determined by experiments examining subcellular localization and effects on protein levels. Loss of Magel2 in PWS may contribute to sleep abnormalities in this disorder, specifically the cycling between different sleep stages.