Breakthrough May
Lead To CJD/BSE Tests
A common blood protein is found to bind to the agents that cause BSE and vCJD, raising hopes of tests and possibly cures.
The first natural molecule that binds to the deformed prions that cause variant CJD and BSE has been found. The identification of the blood protein, by a Swiss team, may explain why prions have such devastating effects on the brain.
It could also lead to new tests for the diseases which can be conducted on living people. It could make it possible to remove prions from donated blood destined for transfusions. And further in the future, it might eventually lead to the first treatments. In diseases such as vCJD, BSE and scrapie, a protein called PrP becomes deformed. It then deforms other PrP proteins, in a chain reaction.
Now a team led by Adriano Aguzzi of the University Hospital of Zurich has discovered that plasminogen, a common protein in blood, binds strongly to the deformed prions that cause scrapie in mice and vCJD in humans - but not to normal PrP. "We were very surprised," Aguzzi says.
Clean blood
There are growing fears that vCJD could be transmitted by contaminated blood products. Already, nearly a dozen countries have banned donations from people who have lived in Britain.
The fact that a common blood protein binds to deformed prions makes it more likely that blood could be infectious.
It might be possible to exploit plasminogen's selective binding abilities to remove prions from the blood plasma used for transfusions. Aguzzi's lab is testing modified versions of plasminogen to try to find one that binds to prions even more strongly than the natural molecule.
Prion test
In the meantime, says Aguzzi, the discovery might help researchers develop faster and more accurate tests for prion diseases.
"We are interested in looking at this," says Bruno Oesch of the Swiss firm Prionics, which makes a widely used test for BSE. The finding could also help the search for a test that can be used on living subjects. At the moment, prion diseases can only be diagnosed with certainty after death.
Martin Fischer, the lead author of the new study, has already been given funding by the Consortium for Plasma Science to develop a plasminogen-based test. The consortium involves companies that make blood products,such as Bayer, Aventis Behring and Baxter Hyland Immuno.
Brain damage
The damage seen in diseases such as vCJD cannot be caused simply by abnormal prions accumulating. The prions must interact with other molecules. "But no natural molecule had ever been found which binds to disease-causing prions, but not the normal form," Aguzzi says.
The ability of prions to selectively bind to plasminogen might explain why they wreak havoc in the brain. Plasminogen is the inactive form of plasmin, a powerful enzyme that dissolves proteins. In the brain, plasmin is thought to allow synapses to remodel themselves, a crucial process for thought and memory.
What's really exciting, says Aguzzi, is that Carlos Dotti and his colleagues at the European Molecular Biology Laboratory in Heidelberg have found that on nerve cells, the molecules that help turn plasminogen into plasmin are located on the same specialised patches of membrane as normal PrP.
Aguzzi thinks that prions might bind to nearby plasminogen and so interfere with its vital role in nerve function. He hopes to test this theory by seeing whether mice engineered to lack plasminogen, or its various activators, are immune to scrapie.
If prions do their damage by binding to plasminogen, it might be possible to find drugs that block this. The team is already investigating whether prions increase or decrease plasminogen's conversion to plasmin, and whether plasmin destroys prions.
More at: Nature (vol 408, p 479)
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