Identifying an essential interaction for epilepsy

Scientists at the Institute for Bioengineering of Catalonia (IBEC) describe a major step towards the understanding of epilepsy in a paper published in Molecular Biology of the Cell.

In the study, the researchers shed new light on the importance of a neuronal protein known as PrPc, which performs a number of physiological functions in many neural processes. When mutated or misfolded, the pathogenic form of the protein, PrPsc, induces progressive conditions that affect the brain and nervous system, such as Creutzfeldt-Jakob disease and BSE, while in epilepsy it appears that the healthy protein plays a preventative role.

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Previous studies by the group, who collaborated with clinicians and cellular signalling specialists in Barcelona for this latest paper, had shown that PrPc modulates the action of one of the so-called kainate receptors, GluR6, that plays a critical role in the regulation of the activity of synaptic networks. “PrPc in the neuron blocks the GluR6 receptor and impairs its binding with two additional molecules, PSD95 and MLK3, in the neuronal synapse,” explains Patricia Carulla of IBEC’s Molecular and Cellular Neurobiotechnology group, who led the research. “Absence of PrPc, however, allows the formation of this three-molecule receptor complex which in turn leads to activation of the JNK3 pathway, resulting in increased epilepsy and cell death in the hippocampus.”

The researchers determined the final target of GluR6 activation inside cells by working together with cellular signalling specialists to generate knockouts of both PrPc and JNK3 in vivo. “If the PrPc protein and the JNK3 pathway are both absent, the susceptibility to experimental epilepsy is lost: GluR6 goes ahead and binds to the other two molecules, but the JNK3 stage does not follow,” says group leader José Antonio del Río. “This show that PrPc’s modulation of GluR6 activity plays a key role in the activation of the pathway that leads to the disease.”

The group is now speculating that a similar protective effect of PrPc may occur in other brain injuries sharing a similar activation mechanism – where signalling is transmitted downstream via GluR6-PSD-95-MLK3 to the JNK3 pathway – although further studies would be needed to confirm this. “Increased levels of PrPc has been found in stroke patients,” says José Antonio. “Determining its functional roles at the synapse, as well as its specific interactions in normal and pathological conditions, could help us to understand other neurodegenerative diseases or the effects of ischemia (reduced blood-flow) in the brain.”

Source: Carulla P, Bribián A, Rangel A, Gavín R, Ferrer I, Caelles C, Del Río JA, Llorens F. (2011). Neuroprotective role of PrPC against Kainate-induced epileptic seizures and cell death depends on the modulation of JNK3 activation by GluR6/7-PSD-95 binding. Mol Biol Cell, in press