Synthetic Prions Prove Infectious

A research team generated synthetic (nonnaturally derived) prions in bacteria, converted them to amyloid fibrils, demonstrated that the fibrils cause disease in mice (as natural-prion fibrils are believed to do), and showed that this infectivity can be propagated from one mouse to another.

Such results have long been sought to help substantiate the theory that prion protein alone, and not any conventional DNA- or RNA-based agent, causes fatal neurologic conditions such as scrapie in sheep, mad cow disease in cattle, and Creutzfeldt-Jakob disease in people.

Neurology professor Stanley B. Prusiner of the University of California, San Francisco, devised the protein-only theory and in 1997 won the Nobel Prize in Physiology or Medicine for it. Now, he and his coworkers--including UCSF professor of cellular and molecular pharmacology Fred E. Cohen and UCSF professor of pathology Stephen J. DeArmond--have provided what they believe to be compelling evidence for it [Science, 305, 673 (2004)]. They note that synthetic prions could aid future studies of the mechanisms by which proteins form aggregates in prion diseases and other neurodegenerative conditions, such as Alzheimer's and Parkinson's diseases.

"This work is stunning--the final justification for a very well deserved Nobel Prize," comments Christopher M. Dobson, professor of chemical and structural biology at Cambridge University.

Scientists have believed that the prion theory could be corroborated by creating synthetic prions in the laboratory and showing they could cause disease. Prusiner and coworkers have now done that by engineering bacteria to express a fragment of normal prion protein, isolating and purifying the expressed fragment, subjecting it to conditions that induce aggregation (amyloid formation), and injecting the amyloid fibrils into mice engineered to express the identical prion protein fragment. All the treated mice developed neurologic disease one to two years after being inoculated, whereas controls did not. And brain extracts from infected mice caused other mice to catch the same type of disease.

"For the first time, we can create prions in the test tube," Prusiner says. The work should help researchers "move one step further in understanding how misprocessing [of such proteins] is spontaneously initiated and how it progresses."

Questions have been raised about the study's methodology. "It's impossible to prove unequivocally that there is not something else in the synthetic prion material that's causing infection, so this study isn't going to make all doubters of the protein-only theory vanish," says neurology professor Peter T. Lansbury Jr. of Harvard Medical School. "But I've been waiting for this kind of result for a long time, and I'm thrilled to learn it's been obtained. It's a great experiment and an incredible accomplishment."