Stanley Prusiner knows the middle and the end of the prion disease story, but the beginning continues to elude him.
The scientist, who is credited with identifying aberrant proteins he named prions, admits he has no idea what triggers these pathogens or how they multiply to cause degenerative diseases in mammals such as BSE, Creutzfeldt-Jakob disease, chronic wasting disease and scrapie.
These diseases have the same style in which proteins are not processed properly, accumulate and cause brain malfunction, but the how and why remain unclear, Prusiner said.
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“All these diseases are in the wastebasket of unknown causes,” he said during a lecture at the University of Calgary Oct. 25.
He explained through pictures how these rogue proteins affect the brains of humans and other mammals and possible paths these pathogens may take at the molecular level that lead to a death sentence for the individual.
Prusiner, as director of the Institute for Neurodegenerative Diseases and professor of neurology at the University of California, along with others, has linked Alzheimer’s, Parkinson’s, Lou Geherig’s and Huntington’s diseases as disorders in protein processing in the body. Protein malfunction diseases may affect one out of 10,000 individuals.
“It is not as rare as it would seem,” he said.
In 1997, Prusiner won the Nobel Prize for his work on fatal neurological diseases. His work in prions goes back to 1982 and by the mid-1990s it became clear there was a distinct strain of prion called PrPc that can adopt different conformations that may lead to a killer disease.
At one time diseases like scrapie were thought to be connected to viruses. The disease was eventually linked to PrPc, which changed to another form called PrP scrapie.
“We don’t have a clue where PrPc is converted into PrP scrapie,” Prusiner said. “We are ignorant at this point.”
Nor do researchers know why it takes different spans of time for a disease to appear. In Huntington’s disease, a person is born with the mutation but it may take many years before it manifests itself. Other diseases do not reveal protein mutations.
“About 90 percent of the people who get ALS, Parkinson’s and Alzheimer’s don’t carry mutations,” he said.
It is also known that low levels of PrP scrapie can be cleared by a cell, but as the disease worsens, the body cannot remove it and it appears to move on to other cells.
Scientists have learned that the less stable forms of prion strains appear to move rapidly while stable forms produce disease more slowly.
Mice and hamsters are used in most of the work examining the progression of the disease. One experiment placed a fine wire in the brain of an infected animal.
After 30 seconds of exposure, the infection was clinging to the wire, so Prusiner suggests there could be infectivity carried on neurological surgical instruments.
Other work focuses on finding drugs that might stop the formation of prions. A drug called quinacrine has been most promising but it does not cross the blood to brain barrier well, so further work is examining ways of offering it orally in high doses.
So far researchers have found only one disease-causing prion in mammals but there appear to be as many as four different infectious prions in yeast. Prusiner predicts more will be found as testing improves.
There are no broad generic tests available for recognizing prions or to measure shifts in prions to find precursors to disease.
