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Discovery of a New Function of the Prion Protein Improves our Understanding of Epilepsy

23 November 2009 IBEC - Institute for Bioengineering of Catalonia

Cellular prion protein (PrPc) plays an essential role in maintaining neurotransmitter homeostasis in the central nervous system. This discovery has been made possible by the observation that both a deficiency and an excess of the protein have a considerable effect on this homeostasis. Surprisingly, in both cases, the central nervous excitability threshold is altered to such an extent that an epileptic seizure may result. Thanks to this discovery, we now have more tools at our disposal that can help us to deepen our basic understanding of epilepsy.

The discovery, carried out by researchers of the Institute for Bioengineering of Catalonia (IBEC) and the University of Barcelona (UB), led by José Antonio Del Río, with the collaboration of researchers at Pablo de Olavide University and the National Institute for Food and Agriculture Technology Research, was presented in a study published in PLoS ONE.

Neurotransmitter homeostasis is achieved through a balance between those mechanisms that excite the neurons of the central nervous system and those that inhibit them. In the study, it was observed in laboratory animals that when PrPc is absent, the excitatory mechanisms are altered and epileptic seizures may occur. As under normal conditions the protein is found in adequate concentrations, it was expected that greater amounts of PrPc would provide greater protection against seizures.. Surprisingly, however, the study showed that this is not the case. With an excessive amount of the protein, the level of excitability of the central nervous system is increased even more than in the absence of PrPc, due to the fact that both the excitatory and inhibitory mechanisms are altered. Such alterations further increase the possibility of suffering severe epileptic seizures. These results allow us to conclude that the protein, when present at adequate concentrations, is essential for maintaining neurotransmitter homeostasis or equilibrium in the central nervous system.  

The researchers of IBEC and the UB who participated in the study are currently involved in  developing a description of the possible differences in the expression and modification of the cellular prion protein in epileptic patients.

Gene Regulation

The study published in PLoS ONE also found a correlation between the differential susceptibility induced by alterations in PrPc levels and the gene expression of the excitatory and inhibitory neurotransmitter receptors of the cerebral cortex. It was conducted using transcriptomic microarray analysis, which made it possible to identify a set of 129 co-regulated genes in the absence and overexpression of the protein in the brains of laboratory animals. The analysis of the canonical pathways associated with these co-regulated genes and its subsequent validation made it possible for the first time to determine that both the absence and the overexpression of PrPc affect the levels of expression of glutamate receptors (AMPA-Kainate—an excitatory neurotransmitter) and of  GABA (GABAA—an inhibitory neurotransmitter). Finally, the effects of the differential regulation were corroborated by electrophysiological techniques that are pioneering in Spain.

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