What is a prion? Specifically, what is known about the molecular structure of prions and how they cause infections such as Creutzfeldt-Jakob disease?

Susan Lindquist is a researcher at the Howard Hughes Medical Institute, located in the department of molecular genetics and cell biology at the University of Chicago. She responds:

"'Prion' is a term first used to describe the mysterious infectious agent responsible for several neurodegenerative diseases found in mammals, including Creutzfeldt-Jakob disease (CJD) in humans. The word itself derives from 'proteinaceous infectious particle'; it refers to the initially heretical hypothesis that the infectious agent causing those diseases consists only of protein, with no nucleic acid genome. (All previously known pathogens, such as bacteria and viruses, contain nucleic acids, which enable them to reproduce.) The prion hypothesis explained why the mysterious infectious agent is resistant to ultraviolet radiation, which breaks down nucleic acids, but is susceptible to substances that disrupt proteins.

"A major breakthrough occurred when researchers discovered that the infectious agent consists primarily of a protein found in the membranes of normal cells, but in this case the protein has an altered shape, or conformation. Some scientists hypothesized that the distorted protein could bind to other proteins of the same type and induce them to change their conformation as well, producing a chain reaction that propagates the disease and generates new infectious material. Since then, the gene for this protein has been successfully cloned, and studies using transgenic mice have bolstered the prion hypothesis. The evidence in support of the hypothesis is now very strong, though not incontrovertible.

"Research on prion diseases has recently accelerated for several reasons. First, the mounting experimental evidence has generated great interest in what appears to be a totally new kind of mechanism of disease. Second, the demonstration that prions are responsible for 'mad cow' disease (bovine spongiform encephalopathy), which has infected large numbers of cattle in Great Britain and panicked the public, has lent new urgency to the quest for a cure--especially since the discovery that infected cows might be responsible for several new cases of CJD in humans. Finally, I and my colleagues have recently determined that a phenomenon much like prion infection exists in yeast.

"In the case of yeast, the phenomenon involves the passing of a particular genetic trait from mother cells to daughter cells, rather than the transmission of an infectious agent from one individual to another. These genetic traits had been known for many years, but their baffling patterns of inheritance (for example, they can be passed along through a cell's cytoplasm, rather than the nucleus where the DNA resides) had eluded explanation. We now know that the genetic trait is transmitted by proteins that are encoded in the nucleus but that can change their conformation in the cytoplasm. Once this change has occurred, the reconfigured proteins induce other newly made proteins of the same type to change their conformation, too. Molecular genetic research on yeast should speed up the resolution of fundamental questions about the workings of protein-folding chain reactions. And more important, it suggests that the prion mechanism is ubiquitous among living things and may be responsible for many phenomena other than neurodegenerative diseases like CJD."

Mark Rogers in the department of zoology and the Biotechnology Centre at University College, Dublin, adds some further information:

"The term 'prion' was coined by Stanley B. Prusiner of the University of California School of Medicine at San Francisco in 1982 to distinguish the infectious agent that causes scrapie in sheep, Creutzfeldt-Jakob disease (CJD) in humans and bovine spongiform encephalopathy (BSE) in cattle from other, more typical infectious agents. The prion hypothesis postulates that these diseases are caused not by a conventional virus or bacterium but by a protein that has adopted an abnormal form.

"The process by which this change occurs is not clear and there is a great deal of work under way to establish the structure of the prion protein in both its normal and aberrant forms. Recently scientists have developed a molecular model of both variants and have published papers describing the structure of prion proteins (as manufactured by E. coli bacteria that were altered through recombinant DNA techniques). Further work using magnetic resonance imaging and x-ray crystallography should help us understand the key structural elements that allow the prion to co-opt the normal cellular form into the disease-producing variant. It is likely that other cellular components assist in this process, so work on understanding the cell biology of both forms of the protein is also vital."

Shaun Heaphy in the department of microbiology and immunology at Leicester University provides this overview:

"A number of fatal neurodegenerative diseases in humans--such as Creutzfeldt-Jakob disease (CJD), kuru and Gerstmann-Str¿ussler-Scheinker (GSS) disease--are thought to be caused by an infectious agent known as a prion. Prions also cause disease in a wide variety of other animals, including scrapie in sheep and bovine spongiform encephalopathy (BSE) in cows. Collectively these diseases are known as transmissible spongiform encephalopathies.

"The cause of CJD was unknown for many years; it occurred seemingly randomly, at a very low incidence. In the 1950s an epidemic transmissible disease called kuru, similar to CJD, was identified in the Fore tribe of Papua New Guinea. Transmission of the disease occurred during a ritual funeral process in which the brain of a dead tribe member was removed from the skull, cooked and eaten. Scientific analysis of the brains of people who had died from CJD or kuru showed that their brain tissue had a spongiform appearance, that is, there were holes where cells ought to be, indicating an encephalopathy, or reduction in the number of brain cells.

D. Carleton Gajdusek, working at the U.S. National Institutes of Health, demonstrated that extracts of brain prepared from people who had died of CJD or kuru could cause a similar disease when inoculated into the brain of chimpanzees. These experiments obviously suggested the presence of an infectious agent. That inference has been confirmed by the inadvertent transmission of CJD to patients undergoing various medical treatments, such as corneal transplants and human growth hormone therapy.

"Confusingly, researchers also recognized that some prion diseases, such as GSS, were inherited. The pattern of inheritance was recognized as being autosomal and dominant, meaning that if a parent developed GSS, there was a 50 percent chance that a child of either sex would also develop the disease. Any explanation for the cause of a prion disease therefore has to account for random, inherited and transmitted variants of the disease.

"Although there is not yet a universally accepted explanation of this puzzle, progress is being made. We now know that a normal cellular protein, called PrP ( for proteinaceous infectious particle) and which is found in all of us, is centrally involved in the spread of prion diseases. This protein consists of about 250 amino acids.

"Some researchers believe that the prions are formed when PrP associates with a foreign pathogenic nucleic acid. This is called the virino hypothesis. (Viruses consist of proteins and nucleic acids that are specified by the virus genome. A virino would also consist of proteins and nucleic acids, but the protein component is specified by the host genome, not the pathogen genome). In support of the virino hypothesis is the existence of different strains of prions that cause differing patterns of disease and breed true; the existence of strains in pathogens is usually the result of changes in the nucleic acid sequence of the infectious agent. Scientists have not found any nucleic acid associated with a prion, however, despite intensive efforts in many laboratories. Furthermore, prions appear to remain infectious even after being exposed to treatments that destroy nucleic acids.

"This evidence has led to the now widely accepted prion theory, which states that the cellular protein PrP is the sole causative agent of prion diseases; there is no nucleic acid involved. The theory holds that PrP is normally in a stable shape (pN) that does not cause disease. The protein can be flipped, however, into an abnormal shape (pD) that does cause disease. pD is infectious because it can associate with pN and convert it to pD, in an exponential process--each pD can convert more pN to pD.

"Prions can be transmitted, possibly by eating and certainly by inoculation either directly into the brain or into skin and muscle tissue. Exponential amplification of the prion (converting pN into pD in the body) would then result in disease. Occasional, sporadic cases of prion diseases arise in middle or old age, presumably because there is a very small but real chance that pN can spontaneously flip to pD; the cumulative likelihood of such a flip grows over the years. Inherited cases of CJD and GSS may result from mutations in the PrP gene, which gives rise to changes in the amino acid sequence of the PrP protein. This change would increase the probability of pN transforming into pD, so that the disease would almost certainly occur.

"Physical analysis of the structure of PrP provides some direct evidence for the existence of two different (normal and aberrant) shapes. Recently the structure of the core part of the PrP protein was determined by magnetic resonance image analysis. Mutations that cause prion disease are clustered within or adjacent to key structural elements in the protein, so it is easy to imagine that mutations destabilize the structure of pN and cause it to reconfigure into pD.

"The prion theory has not been proved correct, but much evidence now supports it. We do not yet know why the pD structure of a prion would result in neurodegeneration, but we do know that prion protein accumulates in brain tissue. One part of the prion protein can cause apoptosis, or programmed cell death; perhaps this mechanism explains the pattern of the disease.

"Prions have long intrigued scientists because of their unusual properties. Recently the general public has become interested in them as well because of the epidemic of BSE, more dramatically known as mad cow disease. Hundreds of thousands of infected animals have been eaten by Europeans and particularly the British over the past 10 years. The latest research suggests that the infected meat may pose a threat to human health, but the significance of that threat may not become apparent for years. Although it is generally considered a British problem, BSE is almost certainly a natural disease of cattle, so it is undoubtedly found in other countries as well. The normal incidence of BSE is vanishingly small, however. The U.S. Department of Agriculture claims that BSE has not been identified in any U.S. cattle.

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