Generally, prions are limited to a specific host and a few related species. But prions sometimes cross the species barrier to infect new hosts. Notably, prions from cows have hopped to humans, causing disease in 208 people, mostly in the UK. Now, scientists wonder if the prion-induced chronic wasting disease (CWD), which afflicts elk and deer in the US, could jump to humans. Since prion diseases have long dormant periods, the fact that there are no human cases of CWD doesn't necessarily indicate that people won't develop symptoms in the future. "At this point, we cannot predict the species barrier just by looking at the sequence" of the prion protein, Soto says. But his laboratory has developed a test-tube method, analogous to the polymerase chain reaction for DNA, to amplify prions. Their protein misfolding cyclic amplification (PMCA) protocol starts with a minute amount of prion protein and an excess of normal PrP from healthy brain extract. Over repeated cycles of incubation (allowing the proteins to interact) and sonication (to break those interactions and allow the malformed prions to access other normal protein), the process makes more and more infectious protein.
In the current study, Soto and his colleagues show that the technique allows hamster prions to convert mouse proteins, and vice versa. Although prion infections can pass between hamsters and mice in vivo, the process takes years and only some animals develop disease. "Here, we crossed the barrier between hamsters and mice in a couple of weeks in vitro," Soto says. "In our technology, it's actually more efficient than real life." "It is exciting and interesting that a well-characterized, naturally occurring species barrier to prion infection can be breached without mutation of the PrP sequence," says biochemist Surachai Supattapone, who researches prions at Dartmouth Medical School in Hanover, New Hampshire, and was not involved in the study. "It is also interesting that the newly produced prions display novel strain properties, because this observation is consistent with the idea that naturally occurring prion strains might arise as a result of cross-species transmission." Whereas PrP has one healthy conformation, there are multiple possible shapes that cause health problems. In the study, the new prions caused disease within different time frames, affected different areas of the brain, and showed different resistance to protein-digesting enzymes compared with the original strains. This suggests that new kinds of prion, with potentially differing characteristics, can be born every time a misfolded prion protein lands in a new species.
September 16, 2008
Original web page at Nature