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In just the past few decades, amazing discoveries have been made concerning the infectious agents responsible for neurodegenerative diseases known as spongiform encephalopathies, of which some better-known examples are scrapie (in sheep), mad cow disease, and Creutzfeld-Jakob disease (in humans). Such diseases manifest themselves in loss of coordination and dementia, along with other disease-specific symptoms (8). Although initially regarded with skepticism, continuing research has caused scientists to come to accept the possibility, and, indeed, probability, of the existence of a group of pathogens different from all previously identified infectious agents (bacteria, viruses, fungi, parasites). What follows is a brief treatment of these newly discovered pathogens, known as prions, including their unique attributes, molecular structures, modes of infection and propagation, as well as some of the foci of current research.
The term "prion" is short for proteinaceous infectious particle, so named by the man responsible for their discovery, Stanley B. Prusiner, the winner of this year's Nobel Prize for Medicine. What makes prions so unique and intriguing to scientists is the fact that, unlike all other known types of pathogens, they contain no nucleic acids (DNA or RNA) but consist primarily of protein (3). Until then, it was firmly believed that nucleic acids were necessary in order for the infectious agent to reproduce and thus spread the infection in its host (3, a href=#8">8); prions, however, spread infection by causing conformational changes in surrounding proteins, causing them to adapt their own shape and thus become agents of infection themselves. Yet another attribute of prions which initially sparked criticism in the scientific community is the fact that they have more than one way of infecting a host. However, current research strongly supports all of the claims made by Prusiner, and prions have recently been accepted as 'new' members of the pathogen family (10).
Rather than being foreign invaders of their hosts, prions are present in every animal that has been studied so far, found as normal components of neural tissue in particular, but also in various other tissues throughout the body (3). As it turns out, they exist in at least two forms, a harmless, indeed useful, cellular form and the form that causes disease. These two forms of the prion protein (PrP) have been named PrPC (C=cellular) and PrPSc (Sc=scrapie) (3). Because the amino acid sequences of PrPC and PrPSc are often identical, the cause of their functional differences is attributed to their difference in structure, and not to any chemical dissimilarity (4, 8). Whereas PrPC consists primarily of alpha helices and very few beta sheets, PrPSC, though having the same primary structure, consists in large part of beta sheets (5, 8). As yet, it is still unclear exactly what causes the flip from PrPC to PrPSc; however, since there appear to be no chemical dissimilarities, it is believed that the change occurs after the amino acid sequence has been established through an unknown chemical process which does not alter the sequence (4). It does, however, appear to alter some of the bundles (moieties) attached to the protein. This substitution is thought to destabilize the structure of the normal prion, making it more susceptible to conformational change (5, 8). After the transformation of one prion, the process continues at an exponential rate (discussed below), eventually infecting the entire brain of the host and causing irreparable damage (4).
In addition to the mode of infection outlined above, that is, through sporadic conformational transformation, infective prions can also be transmitted from one individual to another during medical procedures such as tissue transplantation and injection of growth hormones, as well as contaminated surgical instruments (4). It is not yet clear whether consumption of infected tissue from another species can result in infection (see discussion of species barrier below). Yet a third mode of infection is through the inheritance of mutated genes that increase the likelihood of conformational change in the prions for which they are responsible (4).
One of the most surprising features of infective prions is their ability to multiply without nucleic acids. They do this by causing otherwise harmless PrPC in their surroundings to adopt their own shape (4, 5, 9. Thus, the spread of infection occurs at an exponentially increasing rate, as each newly shape-changed prion attacks other normal ones around it. Just how this occurs is not yet certain; however, computer models which predict PrPC's most probable structure (based on its amino acid sequence) suggest that it is structurally is less sturdy than PrPSc, which has a higher resistance to cellular proteases, enzymes which degrade proteins (4, 8.
Once PrPC adopts the beta-sheet structure of PrPSc, it becomes detached from the cell membrane and is absorbed by vesicles within the cell (4). In particular, it begins to accumulate in the cell's lysosomes, vesicles containing proteolytic enzymes responsible for the breakdown of proteins and other cellular components (4). The accumulation of PrPSc in the lysosomes causes them to swell and eventually burst, thereby releasing the damaging proteolytic enzymes and PrPSc into the cell (4). As this process is occurring simultaneously in multiple cells, the entire brain gradually becomes riddled with dead and dying nerve-cells, lending it the spongiform appearance that characterizes prion diseases (4).
The precise function of prions in the brain has not yet been ascertained; however, studies done on mice indicate that the function of normal cellular prions may be to prevent the very phenomenon observed in the presence of infectious prions--the gradual wasting away of the brain (7). Such studies have shown that brain degeneration occurs (in mice, at least) not only when PrPSc is present, but also in the absence of both PrPC and PrPSc (7). Although this indicates a protective role for PrPC, it has also been discovered (in mice) that excessive amounts of PrPC in the brain can cause neurodegeneration and destruction of muscles and peripheral nerves (2).
One topic under current research is the ability of prions to be transmitted from a member of one species to an individual from another, also known as the species barrier. The determining factor seems to be the degree of similarity between the two species' prions (7, 8. A great deal of anxiety has been caused by the outbreak in recent years of an epidemic of bovine spongiform encephalopathy (mad cow disease). If one compares the overall evolutionary relationship of humans and cows, the general features of prions, there seems to be little cause for worry; however, human and bovine prions do share two biochemical features in a region of the prion which is suspected to play an important role in transmission (7, 8. These similarities are particular to humans and cows and are not present in more closely related species, such as sheep (7). It is, therefore, possible that bovine prions might be similar enough to human prions to be able to cross the species barrier and infect human hosts with what was originally a bovine disease.
Other hot topics in research are possible treatments for prion diseases. Such treatments would address the structural instability which leads to conformational changes in normal cellular prions (6, 8). As mentioned earlier, PrPC is believed to be composed mainly of alpha helices; research suggests that its overall structure is centered around four core helices (5). Once more is known about the chemical modification process which causes PrPC to convert to PrPSc, researchers hope to create a drug which would position itself in the 'pocket' formed by these four helices, thereby adding stability to the overall structure (6, 8). Other projects currently underway involve the production of more efficient means of producing sample sizes for laboratory research, as well as new techniques for detecting and analyzing prions over a wide variety of species (6).
Clearly, the discovery of prions and their identification as both carriers and catalysts of infectious diseases has been a major scientific breakthrough; moreover, it is an important reminder to humans of the inexhaustible creativity of life, which we should not ever presume to fully understand.
3) Evidence for prions as proteinaceous agents of disease, from Lake Forest College
9)9> "What is a prion? Specifically, what is known about the molecular structure of prions and how they cause infections such as Creutzfeld-Jakob disease?", from Scientific American's Ask the Experts.Serendip