Normal prion protein functions as signal transducer
New study in Science finally finds a role for the normal version of the scrapie prion
The scrapie prion protein (PrPsc), which is a mutated form of the prion protein (PrPc), is well known for its ability to wreck havoc in the brains of humans, sheep, and cows with so-called spongy brain diseases. Yet the ubiquity of the normal form of the protein in the nervous system suggests that it has a function as well, though what it might be is not known. But now, French researchers, reporting in the September 15 issue of Science, have found evidence that it is part of a signal transduction pathway.
Normal prions, which are glycosylphosphatidylinosital-anchored cell surface proteins, appear to participate in a signaling cascade that activates an enzyme called Fyn, a tyrosine kinase that stimulates multiple intracellular events like a cell's responsiveness to stimuli. This unraveling the signal-carrying pathway of the normal prion could reveal what triggers its activity, and later, how its corrupt form (PrPSc) wrecks cellular processes, causing the neurodegeneration of scrapie, according to Odile Kellermann of the Institute Pasteur in Paris and her collaborator Jean-Marie Launay of Hospital Lariboisière.
The researchers identified two forms of a caveolin-1 protein, and possibly another protein, clathrin, which also appeared to participate in the activation of Fyn. Other cellular partners in the signaling cascade, such as those related to cell differentiation stages, may be identified in the future, they said.
To investigate the prion's signaling ability, the scientists used cloned mouse-stem cells (1C11) that can convert into fully functional neurons. These neuronal cells continuously produce normal prions, and they can differentiate into two types of neuronal cells, serotonergic, which produce and respond serotonin or noradrenergic, which respond to norepinephrine. Only cells with a complete neuronal phenotype exhibited links between the prion protein and Fyn activation, suggesting that differentiation may be required to completely activate the signaling cascade, perhaps because the interaction between the different partners depends on cell development.
The detection of normal prions as a signaling molecule may shed new light on how the accumulation of scrapie prions interferes with the usual function of these proteins. Such insights ultimately might suggest possible treatments for diseased brains.
For more information: S. Mouillet-Richard, Differenciation Cellulaire, CNRS-Institut, Pasteur, 75724 Paris, Cedex 15, France. Tel: 331-45-68-84-65. Fax: 331-40-61-31-94. Email: srichard@pasteur.fr.
Edited by Laura DeFrancesco
Managing Editor, Bioresearch Online
Source: American Association for the Advancement of Science