In 1972, a young neurologist named Stanley Prusiner became fascinated with the disease that was killing one of his patients. Creutzfeld-Jacob disease was said to be caused by a "slow virus" by analogy to scrapie, a disease of sheep. But Prusiner's patient had none of the usual signs of a viral disease; no fever, no elevated white blood cell count, no humoral response.
Prusiner's attentions were turned toward the scrapie agent, after it was reported that it was resistant to UV irradiation and ionizing radiation, treatments that would have been expected to inactivate anything with a DNA or RNA genome. And for scrapie, there was, at least, an assay system, which involved inoculating mice with the agent, and waiting to see which ones died a horrible death. It took about sixty mice and about a year to achieve an endpoint titration of a virus stock. By 1982, Prusiner had developed quicker time-interval assay involving intracerebral inoculation of Syrian hamsters.
Efforts to purify the agent by sedimentation proved fruitless, it smeared throughout a sedimentation gradient. Chromotagraphic columns were no better. The agent seemed to have no discrete size. Progress was slow and Prusiner had difficulty maintaining his funding.
It became apparent that treatments that degrade proteins could decrease the infectivity of the scrapie agent, whereas those that degrade nucleic acids could not. Prusiner thus gave the agent its name, the "prion," the neologism deriving from the words "protein" and "infection." The idea that a protein could be an infective agent naturally made a lot of virologists irate, particularly those who had spent their careers trying to isolate "slow viruses."
By 1983, Leroy Hood's group had achieved a partial amino acid sequence of the prion protein purified in Prusiner's lab. This quickly led to the cloning and sequencing of the gene for the prion protein, in collaboration with Charles Weissmann. In 1997, Prusiner was awarded the Nobel Prize in Physiology or Medicine for his work on prions.
The prion protein turned out to be a normal cellular protein that undergoes a conformational change to a stable, abnormal form, designated PrPsc. The abnormal protein generates similar conformational changes in other proteins of the same type, resulting in long, insoluble fibers, called amyloid plaques. These, in turn, cause irreversible changes in the central nervous system, literally microscopic holes in the brain, or spongiform encephalopathy. Prion proteins turned out to be the cause of not only scrapie and Creutzfeld-Jacob disease, but also "mad cow disease." The latter results from cows being fed the remains of infected cows as a protein supplement. A similar cause is suspected for kuru, a neurological disease that once affected the Fore tribe in New Guinea, known for their cannibalistic practices. Some families are afflicted with a heritable form of spongiform encephalopathy, wherein the abnormal prion accumulates spontaneously.
Prion proteins are present not only in mammals, but also in fungi. Fungal prions also undergo conformational changes, but rather than being necessarily toxic, these changes can be advantageous, and fungi have the ability to reverse them. In a study recently reported in Science, Genjiro Suzuki and colleagues at RIKEN Brain Science Institute discovered a new yeast prion protein designated Mod5. They found that its conversion to an aggregated form regulated a sterol biosynthetic pathway necessary for resistance to antifungal agents. Other altered yeast prions have been found to improve growth under poor nitrogen conditions and to promote transcriptional derepression of multiple genes.