By Sean Henahan, Access Excellence

OXFORD, England (5/1/96)- A series of new studies of the genetics of bovine spongiform encephalopathy (mad cow disease) provides some new pieces in the puzzle of prion diseases.

Prion proteins occur naturally in the brain, but their normal function remains a mystery. When altered in certain ways, prions appear to act as the pathological agents associated with spongiform encephalopathies such as BSE, CJD and scrapie. These `rogue' prions are unusual in that they can convert normal prions into copies of themselves, spreading the disease.

Researchers at the University of Oxford report (1) that the prion proteins of humans and cattle appear to have closer genetic similarities than previously believed. This result has significant implications for the understanding of BSE and the clinically similar human disorder Creutzfeld-Jakob disease (CJD). In particular, it may prompt a reevaluation of the case for a causal link between BSE and CJD.

The researchers compared the nucleotide sequences of the genes of naturally occurring prion proteins in a variety of animals in order to create an evolutionary `family tree'. The cattle prion is, as expected, more closely related overall to that of sheep than to the human form. However, cattle and human prions share two unusual features of their sequences that are not found in sheep prions.

These features take the form of the substitution of one amino acid in the mature prion protein for another at a given position in the sequence: a substitution of histidine in place of tyrosine at position 155, and serine instead of aspartic acid at position 143. The odds of the two otherwise unrelated prion proteins sharing these two substitutions at these precise positions are very long (1.2 in 10,000 against). Both substitutions occur in a region of the gene thought to be involved in the acquisition of prion diseases.

The researchers point out that correlation is not the same thing as causation, but that we should nevertheless "remain attentive to rare events that might be associated with the emergence of what may be a new strain of this disease".

A group of German researchers reports new findings (2) that provide a clue to how infectious prions cause tissue damage. The researchers found that the production of oxygen radicals may be at the root of the disease. It appears the prions cause brain cells known as microglia to increase their production of oxygen radicals. The researchers also found that neurons from mice deficient in the precursor protein that can become transformed into the rogue prion are not destroyed even when microglia are around.

The German research offers a glimmer of optimism for the treatment of prion disease (there is no cure at present). They reported preliminary findings indicating that the effects of the rogue brain cells might be blocked by anti-oxidants such as vitamin E.

At this point researchers are not even sure what the normal role of prions is. A new study (3) by Swiss researchers suggest that the normal brain protein PrP are involved in the regulation of sleep. Their studies show that mice without the PrP gene undergo an alteration in normal circadian rhythms and sleep patterns. In PrP-deficient mice, the daily rhythm maintains a regular rate even when the mice are subjected to total darkness for long periods, rather than drifting as it does in normal mice. Electroencephalogram readings showed that the sleep patterns were far more disturbed and `fragmented' than usual.

The results suggest that PrP plays an important function in the regulation of sleep, a finding that may be connected with the symptoms of the latest prion disease to be recognized, an inherited syndrome called fatal familial insomnia.

Another related study (4) showed that elderly PrP-deficient mice developed ataxia as a result of unusual damage to cells in the motor cortex. Japanese researchers genetically engineered mice that lacked the prion protein in their brains. The mice developed normally until the age of 70 weeks. But at about 70 weeks old, all the mice without prions without exception became easily identifiable by their abnormal gait. The mice had lost most of their Purkinje cells, large branching brain cells in the center of the cerebellum. These cells are known to produce prions. The investigators concluded it was most likely that loss of prion protein in Purkinje cells was the primary cause of the death of these cells. They speculate it could be the loss of normal prion protein that causes the damage in diseases like CJD and BSE. This would mean that prions are important to brain functions and it is the mutation rather than the prion itself that is dangerous.

For a comprehensive discussion of prions and BSE, please see the interview with Dr. FA Murphy in the Newsmaker section of What's News in Access Excellence.

SOURCES:

2. D. Brown et al; Nature, 3/28/96, pp. 345-347.

3. I. Tobler, et al.; Nature, 4/18/96, pp 639-642.

4. Katamine, et al.; Nature 380, 528-531; 1996.

Related information on the Internet

Interview with Dr. FA Murphy, with prion graphics

The Official Mad Cow Disease Home Page(Many Links).

UK-Institute for Animal Health

UK- Institute for Food Health and Technology

Mad Cow: The Science and the Story