Prion

A New Infectious Agent

Prion is an acronym for "proteinaceous infectious particle," a term coined by Prusiner in the early 1980s to describe the nature of the agent causing the fatal brain disorders known as transmissible spongiform encephalopathies (TSE), also called prion diseases. Well-known examples of prion diseases include scrapie in sheep and goats, bovine spongiform encephalopathy (BSE, or "mad cow" disease) in cattle, and Creutzfeldt-Jakob disease (CJD) in humans. Prion diseases are infectious and can also be transmitted to healthy animals by inoculating them with extracts of diseased brain.

In the mid-1960s, Tikvah Alper and colleagues reported that nucleic acid was unlikely to be a component of the infectious agent that causes scrapie. In 1967 J. S. Griffith speculated that the scrapie agent might be a protein capable of "self replication" without nucleic acid. However, Prusiner was the first, in the early 1980s, to successfully purify the infectious agent and to show that it consisted mostly of protein (technically speaking it is a glycoprotein, because it has a sugar group attached). He chose to name the new agent "prion" to distinguish it from viruses or viroids.

The essential protein component of prion was later identified in 1984 as prion protein (PrP), which is encoded by a chromosome gene in the host genome. Researchers concluded that the prion is a new infectious agent that consists mostly of PrP. This view is often referred to as the "protein only" or prion hypothesis. Some scientists find this notion hard to accept and have argued that nucleic acid is needed to carry information necessary for infection. However, no one has been able to demonstrate that either DNA or RNA play a direct role in prion replication.

In 1992 Charles Weissmann and colleagues obtained conclusive evidence for the central role of PrP in the transmission of prion diseases, when they created transgenic mice devoid of the PrP gene. These so-called PrP knockout mice were found to be completely resistant to infection when inoculated with scrapie brain preparations. When the PrP gene was reintroduced into the knockout mice, they once again became susceptible to prion infection.

Role of Protein Conformation

How can a protein such as PrP made by a cellular gene become an infectious agent? Prusiner and associates had found that PrP could exist in two forms, a normal or cellular form (PrP^C) normally expressed at low levels in neurons and other cell types, and an abnormal or scrapie form (PrP^Sc) built up in diseased brain. PrP^C is a cell-surface glycoprotein, the function of which has yet to be established. PrP^C consists of a single polypeptide chain folded into predominantly spiral conformations known as α-helices. These structures give rise to a globular shape that is soluble and can be cleared from the cell by degrading enzymes called proteases.

In contrast, PrP^Sc that has been isolated from diseased brain is rich in an alternative conformation that resembles extended strands. These structures are known as β-sheets. The β-sheet rich PrP^Sc tends to aggregate and is resistant to heat and degradation by proteases. It is assumed that PrP^Sc can initiate the infection process by binding to predominantly-helical PrP^C and converting it into more stable PrP^Sc with β-sheet conformation. This will set off a chain reaction leading to accumulation of large amounts of PrP^Sc to levels that result in brain tissue damage. The conformational conversion from α-helices to β-sheets transforms the benign PrP^C into disease-causing PrP^Sc. This model of conformational conversion provides useful insights into the pathogenesis of prion diseases.

Prion Diseases

Historically, prion diseases have been given distinct names. Scrapie is a naturally occurring prion disease of sheep and goats that was first documented in Iceland during the eighteenth century. BSE or mad cow disease is a prion disease of cattle and is believed to be acquired through scrapie-contaminated foodstuffs. Kuru, a prion disease found among the Fore tribe of New Guinea, was shown by D. Carleton Gajdusek to be transmitted by the consumption of human tissue, particularly brain tissue, during funerary rituals. Gajdusek was awarded the 1976 Nobel Prize in physiology or medicine for this contribution. The early symptom of Kuru is a loss of coordination, followed by mental confusion and, ultimately, death. It has virtually disappeared since 1958, when the practice of eating human tissue was more or less eradicated in New Guinea.

CJD is the most common human prion disease, affecting about one in a million people. The main symptom is dementia, along with other neurological signs. There are three forms of CJD. Sporadic CJD, the cause of which has yet to be found, is a spontaneous disease that accounts for a majority of CJD cases. Familial CJD affects people who carry a mutation in the PrP gene on chromosome 20. The third form, called iatrogenic CJD, is the result of accidental transmission during medical treatments. A newly emerged CJD phenotype, commonly called variant CJD, has occurred in the United Kingdom since 1985. Variant CJD has a unique disease profile, and may result from the consumption of BSE-contaminated meat products. It has been diagnosed mostly in young people who initially seek treatment for psychiatric symptoms. Gertsmann-Sträussler-Scheinker (GSS) syndrome is a familial prion disease resulting from a mutation in the PrP gene. The main symptom of GSS is the loss of coordination and dementia. Fatal familial insomnia (FFI) is another a familial prion disease in which fatal dementia follows the loss of physiological sleep.

Although human prion diseases manifest as three etiologically different forms—spontaneously (sporadic CJD), through inheritance (familial CJD, GSS, and FFI), and by infection (iatrogenic CJD, kuru, and possibly the new variant CJD), they nonetheless share a common pathogenetic event. Within the framework of "protein only" hypothesis, they all involve the protein conformational change that converts PrP^C to pathogenic PrP^Sc. Such a structural change in PrP may be triggered by a rare spontaneous event leading to a sporadic disease, a mutation that causes a familial disease, or exposure to foreign PrP^Sc, leading to an acquired disease. The "protein only" hypothesis provides a plausible mechanism underlying the pathogenesis of all forms of prion diseases. Moreover, it also helps explain the tremendous variability in prion-associated disease phenotypes. Structurally distinct variants of PrP^Sc may accumulate in different regions of the brain and initiate pathogenic changes that may eventually lead to distinct pathology in different areas of the brain, and subsequently the particular disease symptoms.

The concept of the prion and the role of protein conformation in disease pathogenesis have renewed inquiry into the causes of other and more common neurodegenerative disorders, such as Alzheimer's disease, Hunt-ington's disease, and Parkinson's disease. A common hallmark of all these diseases, as in prion diseases, is the conversion of an otherwise soluble and functional neuronal protein into a β-sheet rich and protease-resistant protein that has a higher tendency to aggregate and is harmful to the brain. These common pathogenetic features raise the hope that therapeutic interventions based on the same principles may be effective in all these diseases.

SEE ALSO PROTEIN.

Pierluigi Gambetti

and Shu G. Chen

Bibliography

Cohen, F. E., and S. B. Prusiner. "Pathologic Conformations of Prion Proteins."Annual Review in Biochemistry 67 (1998): 793-819.

Prusiner, S. B. "Molecular Biology of Prion Diseases." Science 252 (1991): 1515-1522.

———. "The Prion Diseases." Scientific American (1995): 48-57.

———. Prion Biology and Diseases. New York: Cold Spring Harbor Laboratory Press,1999.