Prions: Newly Identified Infectious Agent

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Prions: Newly Identified Infectious Agent

Speech

By: Ralf F. Pettersson

Date: December 10, 1997

Source: Presentation speech for the Nobel Prize in Physiology or Medicine at the Karolinska Institute, delivered by Ralf F. Pettersson during the 1997 Nobel Prize in Physiology or Medicine ceremony in Stockholm, Sweden. Available online at 〈http://nobelprize.org/medicine/laureates/1997/presentationspeech.html〉 (accessed September 20, 2005).

About the Author: Ralf F. Pettersson is a professor of microbiology and head of the Ludwig Institute for Cancer Research in Stockholm, Sweden.

INTRODUCTION

Prions, whose name stems from the designation "proteinaceous infectious particles" (abbreviated PrPs), are proteins that are by themselves infectious. The discovery of prions and confirmation of their infectious nature was revolutionary and controversial in microbiology. This is because it overturned a long-held dogma that infections were caused by intact organisms, particularly microorganisms such as bacteria, fungi, parasites, or viruses, which contained genetic material in the form of either deoxyribonucleic acid (DNA) or ribonucleic acid (RNA). Because proteins lack genetic material, the prevailing attitude was that any protein alone was incapable of causing disease.

Prions were discovered, along with their role in the degeneration of brain tissue, by American physician Stanley Prusiner. This work earned him the 1997 Nobel Prize in Physiology or Medicine.

In contrast to infectious agents that are not normal residents of a host, prion proteins are normally present in brain tissue in humans and all mammals studied thus far. Research published in 2004 detected prions in other sites in the body of animal models, leading to the suggestion that prions may be more widespread than previously proposed.

A prion is normally a protein constituent of the membrane that surrounds the cells in the brain. The protein is small, only some 250 amino acids in length, and contains regions that have a helical conformation and other regions that adopt a flat, zigzag arrangement of amino acids.

The prion's normal function is still mysterious. Studies using mutant mice that are deficient in prion manufacture indicate that the protein may help protect the brain tissue from destruction that occurs with increasing frequency as someone ages. Specifically, prions may aid in the survival of brain cells known as Purkinje cells, which predominate in the cerebellum, a region of the brain responsible for movement and coordination.

The prion theory states that the protein is the sole cause of the prion-related diseases, and that these diseases result when a normally stable prion is flipped into a different shape. Regions that are helical and zigzag are still present, but their locations in the protein are altered. This confers a different three-dimensional shape to the protein.

The change in conformation of one prion some-how triggers a shape change in its neighboring prions. Over time, this accumulating altered conformation destroys the structure (and so function) of brain tissue.

PRIMARY SOURCE

Your Majesties, Your Royal Highnesses, Ladies and Gentlemen

This year's Nobel Prize in Physiology or Medicine has been awarded to Stanley B. Prusiner for his discovery of prions—a new biological principle of infection.

What is a prion? It is a small infectious protein capable of causing fatal dementia-like diseases in man and animals. It has been known for approximately a century that infectious diseases can be caused by bacteria, viruses, fungi and parasites. All these infectious agents possess a genome, the hereditary material that provides the basis for their replication. The ability to replicate is essential for the manifestation of the diseases they cause. The most remarkable feature of prions is that they are able to replicate themselves without possessing a genome; prions lack hereditary material. Until prions were discovered, duplication without a genome was considered impossible. This discovery was unexpected and provoked controversy.

Although the existence of prions was not known until the work of Stanley Prusiner, many prion diseases have been previously documented. On Iceland, scrapie, a disease affecting sheep was first described in the eighteenth century. In the 1920s, the neurologists Hans Creutzfeldt and Alfons Jakob discovered a similar disease in man. During the 1950s and 60s, Carleton Gajdusek studied kuru, a disease that was spread through cannibalistic rituals practiced by the Fore people in New Guinea. Presently attention is focused on mad cow disease, which has affected approximately 170,000 cows in Britain. These diseases exhibit common pathologies. They are inevitably fatal due to the destruction of the brains of infected individuals. The incubation times may last for several years, during which the affected regions of the brain become gradually spongy in appearance. Gajdusek discovered that kuru and Creutzfeldt-Jakob disease could be transmitted to monkeys, demonstrating that these diseases are contagious. In 1976, when Gajdusek received his Nobel Prize, the nature of the infectious agent was completely unknown. At this time, these diseases were assumed to be caused by a new unidentified virus, termed a slow or unconventional virus. During the 1970s, no significant advances regarding the nature of the agent were made, that is, not until Stanley Prusiner took on the problem.

Prusiner set out to purify the infectious agent, and after ten years of hard work, he obtained a pure preparation. To his great surprise, he found that the agent consisted only of a protein, which he named prion, a term derived from proteinaceous infections particle. Strangely enough, he found that the protein was present in equal amounts in the brains of both diseased and healthy individuals. This discovery was confusing and it was generally concluded that Prusiner must have arrived at the wrong conclusion. How could a protein cause disease if it was present both in diseased and healthy brains? The answer to this question came when Prusiner showed that the prion protein from diseased brains had a completely different three-dimensional conformation. This led Prusiner to propose a hypothesis for how a normal protein could become a disease-causing agent by changing its conformation. The process he proposed may be compared to the transformation of Dr. Jekyll to Mr. Hyde—the same entity, but in two manifestations, a kind innocuous one, and a vicious lethal one. But how can a protein replicate without a genome? Stanley Prusiner suggested that the harmful prion protein could replicate by forcing the normal protein to adopt the shape of the harmful protein in a chain reaction-like process. In other words, when a harmful protein encounters a normal protein, the normal protein is converted into the harmful form. A remarkable feature of prion diseases is that they can arise in three different ways. They can occur spontaneously, or be triggered by infection, or occur as a consequence of hereditary predisposition.

The hypothesis that prions are able to replicate without a genome and to cause disease violated all conventional conceptions and during the 1980s was severely criticized. For more than ten years, Stanley Prusiner fought an uneven battle against overwhelming opposition. Research during the 1990s has, however, rendered strong support for the correctness of Prusiner's prion hypothesis. The mystery behind scrapie, kuru, and mad cow disease has finally been unraveled. Additionally, the discovery of prions has opened up new avenues to better understand the pathogenesis of other more common dementias, such as Alzheimer's disease.

Stanley Prusiner,

Your discovery of the prions has established a novel principle of infection and opened up a new and exciting area in medical research. On behalf of the Nobel Assembly at the Karolinska Institute, I wish to convey to you my warmest congratulations and I now ask you to step forward to receive your Nobel Prize from the hands of His Majesty the King.

SIGNIFICANCE

How a normally functioning prion is first triggered to become infectious is not yet understood by scientists, but is central to efforts to control the progression of neurological diseases. One theory, known as the virino hypothesis, proposes that the infectious form of a prion is formed when the protein associates with the nucleic acid from some infectious organism. Efforts to find prions associated with nucleic acid, however, have so far been unsuccessful.

If the origin of the infectious prion is unclear, the nature of the infectious process following the creation of the infectious form of the prion is becoming clearer. The altered protein somehow is able to stimulate a similar structural change in surrounding prions. The change in shape is assumed (but not yet proven) to result from the direct contact and binding of the altered and infectious prion with the unaltered and still-normally functioning prions. The altered proteins also become infective and encourage other proteins to undergo the conformational change. The cascade produces proteins that literally clog up the brain cells. The affected cells lose their ability to function and die.

The death of the affected regions of the brain cells produces holes in the tissue. This appearance led to the designation of the disease as spongiform encephalopathy.

It is now generally acknowledged that prion diseases of animals, such as scrapie in sheep and bovine spongiform encephalopathy (popularly dubbed mad cow disease) can cross the species barrier to humans. In humans, the progressive loss of brain function is clinically apparent as Creutzfeldt-Jakob disease, kuru, and Gerstmann-Sträussler-Scheinker disease. Other human diseases that are suspected candidates for a prion origin include Alzheimer's disease and Parkinson's disease.

A prion-like protein has been discovered in yeast. There, it does not have a neurological degeneration. The microorganism is able to transfer genetic information to the daughter cell by means of a shape-changing protein rather than by the classical means of a gene. This finding indicates that prions may be a ubiquitous feature of many organisms, where they may serve vital roles not associated with disease.