Unlike all other infectious agents, prions contain no deoxyribonucleic acid (DNA) or ribonucleic acid (RNA). This radical difference has slowed the understanding and acceptance of the infectious properties of prions since their discovery. Prions are infectious agents composed of protein that cause fatal brain diseases. Prion diseases include scrapie in sheep, "mad cow disease" (bovine spongiform encephalopathy, or BSE) in cattle, and Creutzfeldt-Jakob disease (CJD) in humans. Prion diseases can be transmitted when an organism consumes infected brain material from another organism. This occurred in England (and elsewhere) when cows were fed processed remains of infected livestock. While the cause of most cases of CJD is unknown, a small number of European cases have been correlated with the consumption of contaminated beef.

First called "slow viruses," the unusual nature of these infectious agents became clear from experiments performed in the 1960s. For example, the agents were particularly resistant to sterilization procedures that inactivated bacteria and viruses.

In the early 1980s American neurologist Stanley Prusiner published biochemical purification studies suggesting that these pathogens were composed mainly of one type of protein and were thus fundamentally different—and by implication, far simpler chemically—than conventional infectious pathogens of animals and plants. Prusiner coined the term prion (derived from pro- teinaceous in fectious pathogen) to highlight this distinction. The single protein implicated as the causative agent was named the prion protein, PrP for short. Although the theory was first greeted with skepticism, Prusiner was vindicated by receiving the 1997 Nobel Prize in Biology or Medicine.

Generally, and as first suggested by Norwegian-American chemist Christian Anfinsen, the linear sequence of amino acids in a protein determines its unique three-dimensional structure, or "conformation." This conformation arises from folding of the peptide chain driven by thermodynamic considerations. A normal form of PrP made in healthy animals is called PrP C and follows a predetermined pattern of folding. The folding results in three corkscrew (" α -helical") segments that compact down upon each other to form a globular core region. Surprisingly, analysis of the infectious form of the PrP referred to as PrP Sc reveals a different shape. Compared to PrP C , PrP Sc has a diminished amount of α-helix and an increased amount of another folding pattern called α-sheet, despite the fact that they have the same amino acid sequence.

These findings defined a new mechanism of disease resulting from proteins adopting alternative, inappropriate conformations. The exact means whereby PrP Sc molecules are formed from PrP C molecules is not fully understood. Nonetheless, it appears to involve a templating reaction where PrP C molecules are first unfolded and then refolded into the shape characteristic of PrP Sc using preexisting PrP Sc molecules as templates . Since the generation of new PrP Sc molecules is equated with (and perhaps the same as) the generation of new infectious particles, it can be seen that prions "replicate" in a strange and novel manner, namely by subverting the folding of a normal cell-surface protein.

SEE ALSO Neurologic Diseases ; Protein Structure

David Westaway


Prusiner, S. B. Scientific American 272, no. 1 (January 1995): 48–57.

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