杏吧原创

FOR the first time, a natural molecule that binds to the deformed prions that
cause variant CJD and BSE has been found. The discovery, by a Swiss team, may
explain why prions have such devastating effects on the brain.

If it does, then it might eventually lead to treatments. More immediately, it
could make it possible to remove prions from donated blood destined for
transfusions.

In diseases such as vCJD, BSE and scrapie, a protein called PrP becomes
deformed. It then deforms other PrP proteins. 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鈥攂ut not to normal PrP. 鈥淲e were very surprised,鈥�
Aguzzi says.

The damage seen in diseases such as vCJD cannot be caused simply by prions
accumulating. The prions must interact with other molecules. 鈥淏ut no natural
molecule had ever been found which binds to disease-causing prion, but not the
normal form,鈥� 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鈥攁 crucial process for thought and
memory.

What鈥檚 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鈥檚 conversion to plasmin, and whether plasmin
destroys prions.

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 prions
makes it more likely that blood could be infectious.

It might be possible to exploit plasminogen鈥檚 selective binding abilities to
remove prions from the blood plasma used for transfusions. Aguzzi鈥檚 lab is
testing modified versions of plasminogen to see if one binds to prions even more
strongly than the natural molecule.

In the meantime, says Aguzzi, the discovery might help researchers develop
faster and more accurate tests for prion diseases. 鈥淲e are interested in looking
at this,鈥� 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 study, has already been given funding
by the Consortium for Plasma Science to develop a plasminogen-based test. The
consortium involves companies which make blood products, such as Bayer, Aventis
Behring and Baxter Hyland Immuno.