A UCD research group is looking for new treatments for animal and human forms of mad cow disease. Dick Ahlstrom reports
Stress inside the cell may be a key factor in the development of BSE in cattle and the human form of the disease, Creutzfeld Jacob Disease (CJD). A Dublin based research group hopes to use this to develop new ways to treat these diseases.
The tragedy of BSE was a frightening reminder about how suspect food production practices could lead to illness and death. The disease arose when animal waste left over after factory processing was in turn reconstituted into animal feed and given to livestock. Infected cattle developed the invariably fatal disease but in turn it jumped across to humans, creating a wholly new form of CJD.
There have been two deaths from this new form of CJD in Ireland but almost 150 in Britain. The eventual number of cases we are likely to see remains unknown but studies in the UK suggest it could range from more than 10,000 up to 250,000 for the most pessimistic estimates.
The research by University College Dublin's "prion group" within the Department of Industrial Microbiology therefore becomes very important. The team, led by Dr Hilary McMahon, hopes to find ways not just to halt the development of the disease in animals and humans, but to reverse it.
Dr McMahon returned from a research centre in France to take up a post in her alma mater, UCD. The Health Research Board, the Irish Research Council and Enterprise Ireland fund the work.
"We are trying to identify what factors are involved in the disease and how to cure them," she says. The team has already enjoyed some success, pinpointing an unexpected cause. "One of the factors involved in the disease is oxidative stress." The cattle and human forms and the form found in sheep - scrapie - are known collectively as transmissible spongiform encephalopathies. The disease attacks brain cells and causes sponge-like holes that give it its name. All are also linked to a change in the "prion" protein that occurs naturally in brain cells. The disease converts the normal short-lived prion protein into a non-degradable form that builds up as plaques in the cells. It is known that the normal prions convert to the abnormal form when the two come in contact, thus causing a spiral of disease.
Reactive chemicals involving forms of oxygen that attach to and damage structures inside the cell cause the stress being examined by McMahon's group. These oxygen radicals arise naturally when we digest foods but are also produced by exposure to radiation, chemicals and by other causes.
The body protects itself by producing enzymes that mop up the "superoxide" radicals explains McMahon. "A key enzyme is superoxide dismutase. This is one of the most important enzymes to remove superoxide from the cell." She is using in vitro methods to examine how stress levels in the cell are associated with the progression of scrapie.
"Scrapie is a very good model for looking at other spongiform encephalopathies."
Brain cell lines are used to study the biochemistry behind the disease, tracing each step as cells are overcome. "We found that oxidative stress was involved in the process," says McMahon.
Infected cells had increased levels of "stress molecules", the superoxide forms that can damage proteins and substances inside the cell. At the same time levels of superoxide dismutase fell by half in the tests done so far.
So superoxide levels rose even as levels of the key protection enzyme fell once the disease process was introduced.
She and other groups have now found that the stress molecules alone can cause normal prions to convert into the diseased forms associated with scrapie. There is now speculation, she said, that stress molecules alone might actually cause the rare one or two spontaneous cases of CJD that arise in the Republic in a typical year.
She hopes to find ways to interfere with this conversion process as a way to stop and then reverse the disease. "We are focusing on modifying the trafficking of the normal prion protein," she says. She is also looking at the introduction of "scavengers" to mop up excess oxidative molecules in the cell. "If you can identify a drug that can reverse it you would hope it could also prevent the disease," says McMahon.