Mad cow just got madder in face of multifaceted molecule

By Graeme O'Neill
Tuesday, 11 February, 2003

The story of the so-called prion diseases, including 'mad cow' disease, is one of the strangest in the annals of 20th century medical science -- and it grows stranger still.

Many biologists still recoil from the proposition that devastating brain disorders like Creutzfeldt-Jakob disease, kuru or 'laughing disease', and Gerstmann-Straussler-Schinker syndrome, are caused by infectious agents that have no genetic material -- prions.

At this week's 28th Lorne Conference on Protein Structure and Function, Andrew Hill, of Melbourne University's Department of Biochemistry, described new research that confirms that the same, normal protein molecule can assume four distinct prion identities.

Without any change in its amino acid sequence, the prion precursor protein, PrP, can give rise to prions that cause four clinically distinct forms of CJD, including the notorious variant CJD (vCJD), seen in human patients who ate contaminated beef during Britain's epidemic of 'mad cow' disease in the 1990s.

Hill and his colleagues in Prof John Collinge's laboratory in the MRC Prion Unit in London -- the world's leading centre for research into the diseases -- devised a test that can discriminate between the various forms of CJD.

The advance is significant, given that each new case of CJD can ignite renewed consumer fears and lead to bans on exports of beef and beef products.

New methods of diagnosis

Until recently, vCJD could only be confirmed by a post-mortem analysis of a victim's brain tissues. Hill says the new test can accurately diagnose vCJD from tonsil or lymphatic tissues in living individuals who do not yet exhibit severe symptoms.

The test involves a protease -- a protein-cleaving enzyme -- that cuts the prion molecule into fragments. Depending on which form of the prion is present, Western blotting yields a pattern of three bands on a gel.

The variable size of the fragments between the different forms depends on where the protease cleaves the PrP molecule, and this depends in turn on which regions of the abnormal forms of each protein are exposed to enzymatic cleavage.

The distinction between the three sporadic forms of CJD and vCJD is made on the basis of distinct fragment sizes, and the degree to which each fragment is glycosylated.

Glycosylation, the addition of small sugar molecules to the protein fragment, adds to each fragment's molecular mass, causing it to remain higher on the gel.

In vCJD, an abundance of the highly glycosylated form produces a 'fingerprint' dominated by the uppermost of the three bands. In sporadic CJD, the central band dominates.

Hill says experiments in transgenic mice carrying the human PrP gene, and deliberately infected with either the BSE or vCJD prions, confirm a close, probably causal relationship between the two diseases.

The discovery has yielded an accurate diagnostic test for suspected case of vCJD in Britain, made more important by the fact that the diagnosis can now be confirmed in living patients, via a tonsil biopsy.

-- Graeme O'Neill will continue to report on the latest research from Lorne Protein all this week

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