Prion

I

Introduction

Prion, shortened term for proteinaceous infectious particle, a small protein linked to certain rare, fatal brain diseases in cows, sheep, humans, and other mammals. If the prion is an infectious agent, it is the first infectious agent identified that does not contain the nucleic acids deoxyribonucleic acid (DNA) or ribonucleic acid (RNA). While the prion’s role in causing disease is still controversial, its discovery has opened the door to alternative ideas about how infectious diseases may be transmitted.

Discovered by American neurologist Stanley B. Prusiner, prions are proteins with an abnormal shape, believed to be caused by a mutation to the gene that encodes for the protein. Normal proteins are found on the surfaces of nerve cells in the brain, white blood cells, muscle cells, and cells of many other tissues. The role of the normal protein is not yet understood, but the mystery of its structure has been solved. A hundred times smaller than the smallest virus, the normal protein is composed of 208 amino acids twisted into three long telephone cordlike coils known as helices. A floppy tail of 97 amino acids extends from the end of one of the helices. The abnormal protein is built of the same amino acids. However, instead of the coil shape, the abnormal protein is folded like the flat pleats of a partly opened accordion.

Some scientists think that the abnormal protein causes disease when it contacts the normal protein and triggers part of it to switch from the coiled to the pleated form. A chain reaction follows, resulting in a cluster of tangled, nonfunctional proteins called plaques. These plaques are found in the brains of animals that die from prion-related diseases. The plaques destroy the brain cells, resulting in one of the diseases collectively known as transmissible spongiform encephalopathies (TSEs).

TSEs cause inflammation and characteristic spongelike holes in the delicate membranes surrounding brain cells. This physical damage results in loss of coordination, dementia, and, eventually, death. Perhaps the best-known TSE is bovine spongiform encephalopathy (BSE), more popularly known as mad cow disease. BSE made headlines in 1996 when about a million cattle in the United Kingdom became infected with the disease. Most scientists believe the infection originally spread when cows contracted BSE after eating animal feed containing sheep’s brains and other sheep byproducts infected with scrapie, a fatal spongiform disease affecting sheep and goats. Later, the epidemic spread when brains and other tissues from infected cattle were used in protein supplements distributed to cattle throughout Britain. By 2003 ingestion of the infected cow meat had caused about 150 people in Britain and Europe to develop an unusual form of Creutzfeldt-Jakob disease known as variant Creutzfeldt-Jakob disease (vCJD). Other TSEs include kuru, a rare disease contracted by natives of New Guinea who ate the infected brains of their dead relatives during ritual cannibalism.

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II

Prion Discovery

The road to the discovery of the prion began with investigations into the cause of TSEs. In 1967 British scientist Tikvah Alper and her colleagues at the Hammersmith Hospital in London extracted brain tissue from scrapie-infected sheep. They chemically treated the tissue to isolate a virus, bacteria, or other agent that might cause the disease. This processed tissue was then injected into healthy sheep to see if the disease would be transmitted. The healthy sheep contracted scrapie, indicating that the infectious agent was in the diseased brain tissue. Further, this experiment showed that the infectious agent could reproduce in healthy animals to cause disease.

Alper then exposed similar scrapie-infected tissue extracts to ultraviolet radiation—a treatment that normally destroys DNA and RNA. She found that the extracts maintained their ability to transmit scrapie. The resistance of the infectious agent to ultraviolet radiation suggested that neither a virus nor bacteria, which reproduce through their nucleic acids, caused the disease. Her discovery indicated that a previously unknown kind of infectious agent was responsible for scrapie. Her findings galvanized debate among scientists about the nature of this infectious particle.

In the early 1980s Prusiner, working at the University of California at San Francisco, found that similar tissue extracts no longer caused disease after they were exposed to treatments that destroy proteins. Prusiner concluded in a study published in 1982 that proteins alone were responsible for TSEs. He suggested that proteins cause these diseases by replicating in tissues of the nervous system.

III

Controversy

Prusiner’s revolutionary idea has met with great resistance because DNA and RNA are the only substances now known to replicate in body tissues. The concept of a proteinaceous infectious particle capsized the widely accepted convictions about agents of infectious disease.

Prusiner received the 1997 Nobel Prize in physiology or medicine for his work with prions. Even so, his theory that prions alone produce TSEs remains controversial. Some scientists believe that TSEs are caused by an as yet unidentified slow-acting virus. Some believe that a small virus accompanies a prion, and both are needed to produce scrapie, BSE, and other TSEs. Still other scientists think that other proteins, called “chaperones,” initiate the improper folding of the normal proteins.

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