Involvement of GABAergic and adenosinergic systems in PrPC function associated to sleep and circadian rhythm

Abstract

Prion is an infectious agent that causes neurodegenerative disorder in human and animals. Prion is composed mainly of a protein designated PrPSc, which is partially resistant to proteinase K. PrPSc is generated from endogenous prion protein (PrPC) through the conformational changes which is induced by PrPSc itself. PrPC is a glycoprotein linked to the outer leaflet of the plasma membrane and participates in diverse physiological processes such as cellular differentiation, anti-apoptotic process, signal transduction and inflammatory response. In addition, substantial evidences indicate that PrPC is involved in homeostatic and circadian regulation of sleep. However, the detailed molecular mechanism involved in this process in not elucidated. It is well established that GABAergic and adenosinergic systems play important roles in the regulation of sleep-wake cycle. Interestingly, these neurotransmission systems are altered in patient with prion diseases or in PrPC knockout mice suggesting that PrPC might be a key component that integrate the neurotransmission systems into sleep regulation. Other evidence that support this hypothesis is the high affinity of PrPC for cyclic compounds and oligonucleotides suggesting that PrPC regulates the level of free adenosine and inosine, a regulator of activity of GABA receptor. Base on these findings, the main goal of this project is to determine the role of PrPC in neurotransmission associated to sleep regulation and to identify other molecules involved in this process. This study can improve our knowledge about the pathological process that alters circadian rhythms and sleep patterns of patients with prion disease and generate therapeutic strategies. Moreover, this study can help to reveal the complex molecular mechanism involved in sleep physiology. The association of researcher who has an extensive experience in prion studies to department of psicobiology, one of the most active institutions in sleep research will provide a strong base for this project. (AU)