By Tina Hesman Saey, Science News
Infectious proteins that cause brain-wasting conditions like mad cow disease appear to build up in the brain long before initiating the cascade of deterioration that leads to dementia and death, a new study of mice finds.
The findings suggest that other factors besides the misshapen infectious proteins characteristic of prion diseases may control the lethality of the disease. If scientists can determine what those factors are, future treatments may be able to prevent the infectious protein diseases—which include mad cow disease, scrapie in sheep and Creutzfeldt-Jakob disease in people—from progressing to a fatal stage.
“We don’t know what’s going on here, but we do know there’s something interesting,” says John Collinge, director of the United Kingdom Medical Research Council Prion Unit in London, who headed the new study.
Findings reported by Collinge and his colleagues in the Feb. 24 Nature contradict the idea that infectious versions of a normal brain protein called PrP accumulate slowly, gradually twisting all of the healthy copies of the protein into a disease-causing form. Researchers have thought that the disease-causing prions slowly build up to toxic levels that spell the death of brain cells.
But the new study shows that the process is anything but gradual, and that infection and toxicity are independent stages of the disease. Prions quickly build up in the brains of mice over the course of a month or two, Collinge and his colleagues found, peaking at about 100 million infectious particles per brain.
That level remains constant for months with no evidence of disease.
“Whatever you do, it sort of stops at that level and remains there for the duration of the infection,” says Collinge.
Researchers had expected that if they increased the amount of the normal PrP protein in the mice’s brains, the number of infectious particles would increase as well. But instead, prion levels plateaued. No one knows what stops mice from making ever more infectious particles, but the researchers speculate that there may be some substance that puts a ceiling on the number of prions in the brain.
Although the number of infectious particles in the brain didn’t change, the length of the incubation period between the initial infection and the onset of disease was faster in mice that made more PrP in their brains. The result suggests that how fast an animal will get sick depends upon how much PrP is in the brain.
The lag time between prion build-up and disease suggests that infection is a separate process from toxicity. Collinge and his colleagues speculate that some other as-yet-unknown molecule or cellular process might be needed to make the switch between infectious and toxic prions.
“It’s provocative,” says Reed Wickner, a geneticist at the U.S. National Institute of Diabetes and Digestive and Kidney Diseases in Bethesda, Md., of the study. The idea that some other substance might be needed to convert the prion into a lethal form is “a reasonable suggestion, but there may be other explanations, too,” he says.
He speculates that number of prions in the brain may be limited, but the size of each particle is not. It could be that filaments of prion protein inside cells just keep getting bigger and bigger until they finally become lethal to the cell.
Collinge agrees that the size of the prion filament may matter, but says that the new research clearly shows that prions don’t directly kill brain cells. Another possibility is that the production of prions depletes some important factor from brain cells, he says. When that substance is used up, cells die.
He and his team are now trying to determine if the toxic form of the prion protein is biochemically distinct from the infectious form.