CJD SWITCH

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Sci/Tech

CJD's deadly switch

revealed

Rogue proteins form fatal clumps in the brain

The critical moment when

Creutzfeldt-Jakob disease or BSE

strikes the brain has been captured in

a test tube for the first time.

The breakthrough is a major step

forward for the future development of

new diagnostic tests and possibly

even effective treatments of the fatal diseases.

" It opens up new research directions to understand CJD

and BSE, " said the research leader, Professor

Collinge, Director of the UK's Medical Research

Council's Prion Unit.

" While it leads to the possibility of

developing much better diagnostic

tests, our eventual goal of an effective

treatment for these devastating brain

diseases still remains an enormous

challenge, " he added.

In Britain, 39 people have died of CJD. But the

incubation

period may be as long as 30 years, meaning the final

extent of the disease cannot yet be predicted. A blood

test for CJD could reveal this.

Sharp rise in cases

The research breakthrough comes in the same week

that a sharp rise in confirmed cases (nine) and referrals

of CJD were announced for the last quarter of 1998.

Simon Cousens of the CJD

Surveillance Unit said the

new cases were cause for

concern, but said it was

important to wait until the

end of the year to see if they

represented a trend.

Professor Collinge agreed the

rise was worrying and that it

was " too early to know what

the figures mean " . But he

added that it was still entirely

possible that there could be

a CJD epidemic.

Deadly transformation

His new research has unmasked the mysterious

mechanism by which normal prion proteins in the brain

are transformed into a different, deadly form.

This happens when a rogue

prion corrupts a perfectly

normal prion, PrP, which

usually sits on the surface of

brain cells.

It is believed that the

abnormal prion causes the

normal protein to change

shape to form a new rogue

prion. A domino effect

follows.

The altered proteins cannot dissolve as normal and build

up in hard clumps or " plaques " . This kills the cells they

form in and is also a barrier to scientific analysis of

the

rogue protein's structure.

The protein clumps are the " holes " which characterise

the prion brain diseases and cause the brain damage

which is ultimately fatal.

But just how the prion

persuades the normal protein

to change was until now

completely unknown.

Catching the conversion in

the act allowed the British

scientists to discover that

just one, subtle change is

responsible.

Single bond

" We now know that the

conversion involves breaking

a single bond in the molecule using conditions which

exist normally within cells, " explains Professor

Collinge.

" This remarkable property of prion protein is

unprecedented: no other protein has yet been shown to

be able to exist in two such entirely unrelated shapes. "

The team was convinced they had exposed the

disease's secret when their altered protein formed

clumps which were indistinguishable from the rogue form

found in the brain of CJD and BSE victims.

New drugs

The scientists believe the new information should make

it possible to create antibodies which detect the rogue

protein specifically. This would mean new diagnostic

tests for prion disease in humans and animals.

Also, knowing how the switch from normal to rogue

protein occurs could help researchers develop new drugs

to treat and prevent prion disease.

The research is published in Science magazine and was

funded by the Medical Research Council and the

Wellcome Trust.