Among the most mysterious and virulent diseases known, prion diseases turn the brains of otherwise normal, healthy people into a spongy mush—and, without fail, kill them. While mad cow disease, Creutzfeldt-Jakob disease, fatal familial insomnia, and other prion diseases are exceedingly rare, scientists have spent the past 25 years searching for answers to how an enigmatic protein could cause such destruction. Researchers are now beginning to understand the role that mutant prion proteins play in these brain-wasting diseases, and though the road to a cure is full of obstacles, a bit of the gloom is starting to lift.   

Chain Reaction of Misfolded Proteins

The idea that a protein could be the cause of an infectious disease was revolutionary until the early 1980s, when Stanley Prusiner, M.D., of the University of California–San Francisco School of Medicine introduced the concept of prions, for which he won the Nobel Prize in 1997. Prions, says Prusiner, are “tiny protein molecules that seem to cause a variety of slow-acting and inevitably fatal diseases in animals and humans.” Prusiner named these proteins “prions,” short for “proteinaceous infectious particles.”

Found in the brains of all living animals, prions contain no DNA or RNA, the building blocks of the genetic code. In their normal form, prions are natural components of the body, although their function is still largely unknown. But when they become twisted or folded in large numbers, over time, they lead to diseases that are characterized by holes in the brain where neurons have died and by rapid loss of mental abilities.

Every protein in the body has a specific conformation, or shape, and many of them contain amino acids that allow them to change the shape of other proteins. Prions exist in two distinct conformations in the brain: a “wild type” that everyone possesses and a densely folded, infectious type. The infectious form of the protein recruits wild-type proteins to misfold, causing them to be infectious as well. Once this occurs, a massive chain reaction takes place in which increasing numbers of prions in the brain misfold and become infectious, triggering the cascade of deadly neurodegenerative effects.

These molecular models show how a normal prion protein (top) is folded into a helix, while the infectious disease form (bottom) is misfolded. Credit: © Eurelios/Phototake

In about 85 percent of human prion disease, the misfolding of proteins, called cellular prion proteins (PrPc), into a disease form, or isoform (PrPSc), occurs sporadically.  Another 14 percent of human disease occurs from familial forms, associated with mutations of the gene that encodes prion protein. The remaining one percent of human prion disease is transmitted by eating food made from an infected animal, such as a cow.  Whether sporadic, inherited, or transmitted, prion diseases all induce the buildup in the brain of toxic plaques that cause the widespread death of neurons.