November 12, 2003
PROTEIN AND FREE RADICALS : DANGEROUS LIAISONS
Prions, infectious agents responsible for transmissible spongiform encephalopathies (TSE) -such as Creutzfeldt-Jakob disease in humans, mad cow disease, scrapie, etc.-correspond to the pathological form of a normal prion protein whose function is still mysterious. Researchers from the Institut Pasteur and the CNRS have made a remarkable advance in understanding the physiological role of the normal prion protein by showing that it acts through reactive oxygen species, "free radicals". This discovery should make it possible to understand how the pathogenic form of the prion alters cellular functions and leads to the characteristic neurodegeneration of TSE.
Odile Kellermann and her collaborators (CNRS-Institut Pasteur) reveal in research presented in the 11 November 2003 issue of the journal PNAS that the non-pathogenic prion protein activates an enzyme, NADPH oxidase, that in turn produces free radicals from oxygen that act as intracellular messengers. This cascade leads to the modification of some mediators known for their role in cell proliferation and survival, the ERK proteins. These functions of the prion protein, shown in neurons and other cell types such as lymphocytes, could be common to all the cells of the organism. The authors nevertheless demonstrate a specificity of the neurons' response to the signals associated with the prion protein. The free radicals that, when produced in small quantities, constitute a link in the dialogue between the cell and its environment, are also dangerous molecules known to cause cell death. If the dialogue is disturbed in neurons by the presence of the pathogenic prion, overproduced free radicals could have toxic effects and alter neuronal functions.
This discovery follows research by Odile Kellermann's team, carried out in collaboration with two other French teams and published in 2000 in the journal Science. In their laboratory, the researchers had isolated a cell line able to differentiate into neurons. By using this experimental model, the authors had already shown that the non-pathogenic prion protein takes part in a complex signalling cascade that participates in the fine tuning of neuronal functions. Their further research along this line has made it possible today to define a function for the prion protein.
This research opens up considerable prospects for understanding how neurons respond to infection by prions. Characterizing biochemical targets of the prion protein is an important step that opens the way for developing analytical tools and designing therapeutic strategies able to inhibit the neurodegenerative effects observed in prion diseases.
This research benefited from grants from the "Prion Infections" Scientific Interest Group (SIG), the CNRS and the Institut Pasteur.
- "NADPH oxidase and extracellular regulated kinases 1/2 are targets of prion protein signaling in neuronal and nonneuronal cells" : PNAS, November 2003
Benoît Schneider (1,2), Vincent Mutel (3) , Mathéa Pietri (1,2), Myriam Ermonval (1,2), Sophie Mouillet-Richard (1,2), and Odile Kellermann (1,2)
1 Cellular Differentiation
and Prions, Centre National de la Recherche Scientifique, Unité Propre
de Recherche (UPR) 1983, Villejuif
2 Biology of Host-Parasite Interactions Unit, CNRS URA 1960, Institut Pasteur, Paris
3 Pharma Research Department, F. Hoffmann-La-Roche Ltd., CH-4070 Basel, Switzerland
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