The orexin system in Prader-Willi syndrome

Prader-Willi syndrome (PWS) is a genetic disorder characterized by a number of clinical features, including short stature, poor muscle development, excessive appetite with progressive obesity, mental retardation, behavioural abnormalities and sleep disturbances. Obesity occurs in over 90% of affected individuals and is the most prominent physical characteristic of untreated PWS as well as a major cause of morbidity and mortality. The cause of the features of PWS remains unknown. However, as individuals display many symptoms of a disturbance in the hypothalamus (the lower part of the midbrain), it is believed that some ‘transmitter’ substance in the brain is either absent or malfunctioning. The recent discovery of orexins, from the hypothalamus, may help to shed some light on the features of PWS. Orexins have been shown to stimulate appetite, and therefore play an important part in weight control and energy balance. They have also been shown to play a role in a number of physiological behaviours, modulate sleep-wake cycles, and are implicated in human narcolepsy, which is a condition characterized by excessive sleepiness; interestingly these features are common to individuals with PWS. However, there is not data, to date, describing these important proteins and their receptors through which they function, in the mid-brains (hypothalami) of individuals with PWS. We therefore feel it is important t investigate this. Our proposal employs molecular biology techniques to investigate the expression of orexins and their receptors in the hypothalami of individuals with PWS (and controls), using postmortem tissue. This will be the first time that these receptors will have been attempted to be classified in this condition. We will cross reference our findings across the while genome using DNA ‘chips’ (microarrays). Currently, there is no cure for PWS, and obesity is a major cause of the excess morbidity and mortality seen in these individuals. We envisage that the findings will expand and encourage research into orexin biology in PWS, and bring closer a pharmacological treatment for this disabling condition.