Science: Prion proteins may signal trouble -- literally

This release is also available in French.

PARIS -- A harmless form of the scrapie prion--an abnormally folded protein that leads to brain-degenerating diseases in humans, sheep, and cows--may help regulate nerve-cell functions through cellular signaling, researchers report in the 15 September issue of the international journal, Science.

While irregular prions are the known culprits behind incurable "spongey-brain" diseases, or transmissible spongiform encephalopathies (TSEs), the purpose of normal prions has remained mysterious until recently.

According to research teams directed by Odile Kellermann of the Institute Pasteur in Paris and Jean-Marie Launay of Hospital Lariboisière, unraveling the signal-carrying pathway of the normal prion (PrP^c) will help reveal what triggers its activity, and later, how its corrupt form (PrPS^c) wrecks cellular processes, causing the neurodegeneration of scrapie.

The non-pathogenic prion protein is not known to play a role in a specific cell function, researchers said. But, normal prions may fine-tune neuronal functions at the cellular level, since they are sited at nerve-cell surfaces, particularly in the outstretched arms of neurons called neurites, which collect and integrate information from other neurons.

Normal prions appear to participate in a signaling "cascade" that activates an enzyme called "Fyn," The Fyn enzyme is a tyrosine kinase capable of stimulating multiple intracellular events that change, for example, a cell's responsiveness to other nervous stimuli, said Odile Kellermann and her collaborator, Sophie Mouillet-Richard, lead author of the Science paper.

The research team 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 are known to continuously produce normal prions, and they can differentiate into two types of neuronal cells, which produce and respond to either serotonin or norepinephrine. Only cells with a complete neuronal phenotype exhibited links between the prion protein and Fyn activation. In fact, full cell 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.

The Science study reflects growing interest in signal transduction, which occurs when biochemical signals move or "transduce" from cell to cell, or from a cell's surface to its interior, eventually influencing the expression of genes. Because signal transduction events can alter gene expression, such processes can control tissue differentiation, cell homeostasis (or cell functions), cell death, and disease. By tracing signaling pathways, many hope to identify strategies for preventing diseases, by blocking events along the route.

For related images, please refer to the following page: http://www.eurekalert.org/E-lert/current/public_releases/scipak/prion.html

For more information on signal transduction research, see Science's Signal Transduction Knowledge Environment, http://www.stke.org.)

With Kellermann, Mouillet-Richard, and Launay, collaborators on the Science study were Myriam Ermonval and Claire Chebassier of CNRS and Institut Pasteur; Jean-Louis Laplanche of Hospital Lariboisière; and Sylvain Lehmann of CNRS, all in France.

This research was supported by the Programme de recherche sur les ESST et les prions, France's Ministry for Education.

To receive a copy of this Science paper, call (202) 326-6440, or send e-mail to scipak@aaas.org.