Fifteen years ago I evoked a good deal of skepticism when I proposed that the infectious agents
causing certain degenerative disorders of the central nervous system in animals and, more rarely, in
humans might consist of protein and nothing else. At th e time, the notion was heretical. Dogma
held that the conveyers of transmissible diseases required genetic material, composed of nucleic
acid (DNA or RNA), in order to establish an infection in a host. Even viruses, among the simplest
microbes, rely on such material to direct synthesis of the proteins needed for survival and
Later, many scientists were similarly dubious when my colleagues and I suggested that these
"proteinaceous infectious particles"-or "prions," as I called the disease-causing agents-could
underlie inherited, as well as communicable, diseases. Such dual behavior was then unknown to
medical science. And we met resistance again when we concluded that prions (pronounced "pree-ons")
multiply in an incredible way; they convert normal protein molecules into dangerous ones simply by
inducing the benign molecules t o change their shape.
Today, however, a wealth of experimental and clinical data has made a convincing case that we are
correct on all three counts. Prions are indeed responsible for transmissible and inherited
disorders of protein conformation. They can also cause sporadic disease, in which neither
transmission between individuals nor inheritance is evident. Moreover, there are hints that the
prions causing the diseases explored thus far may not be the only ones. Prions made of rather
different proteins may contribute to other neurodegenerative diseases that are quite prevalent in
humans. They might even participate in illnesses that attack muscles.
The known prion diseases, all fatal, are sometimes referred to as spongiform encephalopathies. They
are so named because they frequently cause the brain to become riddled with holes. These ills,
which can brew for years (or even for decades in humans) are widespread in animals.
The most common form is scrapie, found in sheep and goats. Afflicted animals lose coordination and
eventually become so incapacitated that they cannot stand. They also become irritable and, in some
cases, develop an intense itch that leads them to scrape off their wool or hair (hence the name
"scrapie"). The other prion diseases of animals go by such names as transmissible mink
encephalopathy, chronic wasting disease of mule deer and elk, feline spongiform encephalopathy and
bovine spongiform encephalopathy. The last, often called mad cow disease, is the most worrisome.
Gerald A. H. Wells and John W. Wilesmith of the Central Veterinary Laboratory in Weybridge, England,
identified the condition in 1986, after it began striking cows in Great Britain, causing them to
became uncoordinated and unusually apprehensive. The source of the emerging epidemic was soon
traced to a food supplement that included meat and bone meal from dead sheep. The methods for
processing sheep carcasses had been changed in the late 1970s. Where once they would have
eliminated the scrapie agent in the supplement, now they apparently did not. The British
government banned the use of animal-derived feed supplements in 1988, and the epidemic has probably
peaked. Nevertheless, many people continue to worry that they will eventually fall ill as a result
of having consumed tainted meat.
The human prion diseases are more obscure. Kuru has been seen only among the Fore highlanders of
Papua New Guinea. They call it the "laughing death." Vincent Zigas of the Australian Public Health
Service and D. Carleton Gajdusek of the U.S. National Institutes of Health described it in 1957,
noting that many highlanders became afflicted with a strange, fatal disease marked by loss of
coordination (ataxia) and often later by dementia. The affected individuals probably acquired kuru
through ritual cannibalism: the Fore tribe reportedly honored the dead by eating their brains.
The practice has since stopped, and kuru has virtually disappeared.
Creutzfeldt-Jakob disease, in contrast, occurs worldwide and usually becomes evident as dementia.
Most of the time it appears sporadically, striking one person in a million, typically around age 60.
About 10 to 15 percent of cases are inherited, and a small number are, sadly, iatrogenic-spread
inadvertently by the attempt to treat some other medical problem. Latrogenic Creutzfeldt-Jakob
disease has apparently been transmitted by corneal transplantation, implantation of dura mater or
electrodes in the brain, use of contaminated surgical instruments, and injection of growth hormone
derived from human pituitaries (before recombinant growth hormone became available).
The two remaining human disorders are Gerstmann-Sträussler-Scheinker disease (which is manifest as
ataxia and other signs of damage to the cerebellum) and fatal familial insomnia (in which dementia
follows difficulty sleeping). Both these conditions are usually inherited and typically appear in
midlife. Fatal familial insomnia was discovered only recently, by Elio Lugaresi and Rossella Medori
of the University of Bologna and Pierluigi Gambetti of Case Western Reserve University.
In Search of the Cause
I first became intrigued by the prion diseases in 1972, when as a resident in neurology at the
University of California School of Medicine at San Francisco, I lost a patient to Creutzfeldt-Jakob
disease. As I reviewed the scientific literature on that and related conditions, I learned that
scrapie, Creutzfeldt-Jakob disease and kuru had all been shown to be transmissible by injecting
extracts of diseased brains into the brains of healthy animals. The infections were thought to be
caused by a slow-acting virus, yet no one had managed to isolate the culprit.
In the course of reading, I came across an astonishing report in which Tikvah Alper and her
colleagues at the Hammersmith Hospital in London suggested that the scrapie agent might lack nucleic
acid, which usually can be degraded by ultraviolet or ionizing radiation. When the nucleic acid in
extracts of scrapie-infected brains was presumably destroyed by those treatments, the extracts
retained their ability to transmit scrapie. If the organism did lack DNA and RNA, the finding would
mean that it was not a virus or any other known type of infectious agent, all of which contain
genetic material. What, then, was it? Investigators had many ideas-including, jokingly, linoleum
and kryptonite-but no hard answers.
I immediately began trying to solve this mystery when I set up a laboratory at U.C.S.F. in 1974.
The first step had to be a mechanical one-purifying the infectious material in scrapie-infected
brains so that its composition could be analyzed. The task was daunting; many investigators had
tried and failed in the past. But with the optimism of youth, I forged ahead [see "Prions," by
Stanley B. Prusiner; SCIENTIFIC AMERICAN, October 1984]. By 1982 my colleagues and I had made good
progress, producing extracts of hamster brains consisting almost exclusively of infectious
material. We had, furthermore, subjected the extracts to a range of tests designed to reveal the
composition of the disease-causing component.
All our results pointed toward one startling conclusion: the infectious agent in scrapie (and
presumably in the related diseases) did indeed lack nucleic acid and consisted mainly, if not
exclusively, of protein. We deduced that DNA and RNA were absent be cause, like Alper, we saw that
procedures known to damage nucleic acid did not reduce infectivity. And we knew protein was an
essential component because procedures that denature (unfold) or degrade protein reduced
infectivity. I thus introduced the term "prion" to distinguish this class of disease conveyer from
viruses, bacteria, fungi and other known pathogens. Not long afterward, we determined that scrapie
prions contained a single protein that we called PrP, for "prion protein."
Now the major question became, Where did the instructions specifying the sequence of amino acids in
PrP reside? Were they carried by an undetected piece of DNA that traveled with PrP, or were they,
perhaps, contained in a gene housed in the chromosomes of cells? The key to this riddle was the
identification in 1984 of some 15 amino acids at one end of the PrP protein. My group identified
this short amino acid sequence in collaboration with Leroy E. Hood and his co-workers at the
California Institute of Technology.
Knowledge of the sequence allowed us and others to construct molecular probes, or detectors, able to
indicate whether mammalian cells carried the PrP gene. With probes produced by Hood's team, Bruno
Oesch, working in the laboratory of Charles Weissmann at the University of Zurich, showed that
hamster cells do contain a gene for PrP. At about the same time, Bruce Cheseboro of the NIH Rocky
Mountain Laboratories made his own probes and established that mouse cells harbor the gene as well.
That work made it possible to isolate the gene and to establish that it resides not in prions but in
the chromosomes of hamsters, mice, humans and all other mammals that have been examined. What is
more, most of the time, these animals make PrP without getting sick.
One interpretation of such findings was that we had made a terrible mistake: PrP had nothing to do
with prion diseases. Another possibility was that PrP could be produced in two forms, one that
generated disease and one that did not. We soon showed the latter interpretation to be correct.
The critical clue was the fact that the PrP found in infected brains resisted breakdown by cellular
enzymes called proteases. Most proteins in cells are degraded fairly easily. I therefore suspected
that if a normal, non-threatening form of PrP existed, it too would be susceptible to degradation.
Ronald A. Barry in my laboratory then identified this hypothetical protease-sensitive form. It thus
became clear that scrapie-causing PrP is a variant of a normal protein. We therefore called the
normal protein "cellular PrP" and the infectious (protease-resistant) form "scrapie PrP." The
latter term is now used to refer to the protein molecules that constitute the prions causing all
scrapie like diseases of animals and humans.
Prion Diseases Can Be Inherited
Early on we had hoped to use the PrP gene to generate pure copies of PrP. Next, we would inject the
protein molecules into animals, secure in the knowledge that no elusive virus was clinging to them.
If the injections caused scrapie in the animals, we would have shown that protein molecules could,
as we had proposed, transmit disease. By 1986, however, we knew the plan would not work. For one
thing, it proved very difficult to induce the gene to make the high levels of PrP needed for
conducting studies. For another thing, the protein that was produced was the normal, cellular
form. Fortunately, work on a different problem led us to an alternative approach for demonstrating
that prions could transmit scrapie without the help of any accompanying nucleic acid.
In many cases, the scrapie like illnesses of humans seemed to occur without having been spread from
one host to another, and in some families they appeared to be inherited. (Today researchers know
that about 10 percent of human prion diseases are familial, felling half of the members of the
affected families.) It was this last pattern that drew our attention. Could it be that prions were
more unusual than we originally thought? Were they responsible for the appearance of both
hereditary and transmissible illnesses?
In 1988 Karen Hsiao in my laboratory and I uncovered some of the earliest data showing that human
prion diseases can certainly be inherited. We acquired clones of a PrP gene obtained from a man who
had Gerstmann-Sträussler-Scheinker disease in his family and was dying of it himself. Then we
compared his gene with PrP genes obtained from a healthy population and found a tiny abnormality
known as a point mutation.
To grasp the nature of this mutation, it helps to know something about the organization of genes.
Genes consist of two strands of the DNA building blocks called nucleotides, which differ from one
another in the bases they carry. The bases on one strand combine with the bases on the other
strand to form base pairs: the "rungs" on the familiar DNA "ladder." In addition to holding the
DNA ladder together, these pairs spell out the sequence of amino acids that must be strung together
to make a particular protein. Three base pairs together-a unit called a codon-specify a single
amino acid. In our dying patient, just one base pair (out of more than 750) had been exchanged for
a different pair. The change, in turn, had altered the information carried by codon 10 2, causing
the amino acid leucine to be substituted for the amino acid proline in the man's PrP protein.
With the help of Tim J. Crow of Northwick Park Hospital in London and Jurg Ott of Columbia
University and their colleagues, we discovered the same mutation in genes from a large number of
patients with Gerstmann-Sträussler-Scheinker disease, and we showed that the high incidence in
the affected families was statistically significant. In other words, we established genetic linkage
between the mutation and the disease-a finding that strongly implies the mutation is the cause.
Over the past six years work by many investigators has uncovered 18 mutations in families with
inherited prion diseases; for five of these mutations, enough cases have now been collected to
demonstrate genetic linkage.
The discovery of mutations gave us a way to eliminate the possibility that a nucleic acid was
traveling with prion proteins and directing their multiplication. We could now create genetically
altered mice carrying a mutated PrP gene. If the presence of the altered gene in these
"transgenic" animals led by itself to scrapie, and if the brain tissue of the transgenic animals
then caused scrapie in healthy animals, we would have solid evidence that the protein encoded by the
mutated gene had been solely responsible for the transfer of disease. Studies I conducted with
Hsiao, Darlene Groth in my group and Stephen J. DeArmond, head of a separate laboratory at U.C.S.F.,
have now shown that scrapie can be generated and transmitted in this way [see box on pages 5 6 and
These results in animals resemble those obtained in 1981, when Gajdusek, Colin L. Masters and
Clarence J. Gibbs, Jr., all at the National Institutes of Health, transmitted apparently inherited
Gerstmann-Sträussler-Scheinker disease to monkeys. They also resemble the findings of Jun
Tateishi and Tetsuyuki Kitamoto of Kyushu University in Japan, who transmitted inherited
Creutzfeldt-Jakob disease to mice. Together the collected transmission studies persuasively argue
that prions do, after all, represent an unprecedented class of infectious agents, composed only of
a modified mammalian protein. And the conclusion is strengthened by the fact that assiduous
searching for a scrapie-specific nucleic acid (especially by Detlev H. Riesner of Heinrich Heine
University in Düsseldorf) has produced no evidence that such genetic material is attached to
Scientists who continue to favor the virus theory might say that we still have not proved our case.
If the PrP gene coded for a protein that, when mutated, facilitated infection by a ubiquitous virus,
the mutation would lead to viral infection of the brain. Then injection of brain extracts from the
mutant animal would spread the infection to another host. Yet in the absence of any evidence of a
virus, this hypothesis looks to be untenable.
In addition to showing that a protein can multiply and cause disease without help from nucleic
acids, we have gained insight into how scrapie PrP propagates in cells. Many details remain to be
worked out, but one aspect appears quite clear: the main difference between normal PrP and scrapie
PrP is conformational. Evidently, the scrapie protein propagates itself by contacting normal PrP
molecules and somehow causing them to unfold and Bip from their usual conformation to the scrapie
shape. This change initiates a cascade in which newly converted molecules change the shape of
other normal PrP molecules, and so on. These events apparently occur on a membrane in the cell
We started to think that the differences between cellular and scrapie forms of PrP must be
conformational after other possibilities began to seem unlikely. For instance, it has long been
known that the infectious form often has the same amino acid sequence as the normal type. Of
course, molecules that start off being identical can later be chemically modified in ways that alter
their activity. But intensive investigations by Neil Stahl and Michael A. Baldwin in my laboratory
have turned up no differences of this kind.
One Protein, Two Shapes
How, exactly, do the structures of normal and scrapie forms of PrP differ? Studies by Keh-Ming Pan
in our group indicate that the normal protein consists primarily of alpha helices, regions in which
the protein backbone twists into a specific kind of spiral; the scrapie form, however, contains
beta strands, regions in which the backbone is fully extended. Collections of these strands form
beta sheets. Fred E. Cohen, who directs another laboratory at U.C.S.F., has used molecular modeling
to try to predict the structure of the normal protein based on its amino acid sequence. His
calculations imply that the protein probably folds into a compact structure having four helices in
its core. Less is known about the structure, or structures, adopted by scrapie PrP.
The evidence supporting the proposition that scrapie PrP can induce an alpha-helical PrP molecule to
switch to a beta-sheet form comes primarily from two important studies by investigators in my group.
Mar'a Gasset learned that synthetic peptides (short strings of amino acids) corresponding to three
of the four putative alpha-helical regions of PrP can fold into beta sheets. And Jack Nguyen has
shown that in their beta-sheet conformation, such peptides can impose a beta-sheet structure on
helical PrP peptides. More recently Byron W. Caughey of the Rocky Mountain Laboratories and Peter
T. Lansbury of the Massachusetts Institute of Technology have reported that cellular PrP can be
converted into scrapie PrP in a test tube by mixing the two proteins together.
PrP molecules arising from mutated genes probably do not adopt the scrapie conformation as soon as
they are synthesized. Otherwise, people carrying mutant genes would become sick in early childhood.
We suspect that mutations in the PrP gene render the resulting proteins susceptible to Bipping from
an alpha-helical to a beta-sheet shape. Presumably, it takes time until one of the molecules
spontaneously Bips over and still more time for scrapie PrP to accumulate and damage the brain
enough to cause symptoms.
Fred Cohen and I think we might be able to explain why the various mutations that have been noted in
PrP genes could facilitate folding into the beta-sheet form. Many of the human mutations give rise
to the substitution of one amino acid for another within the four putative helices or at their
borders. Insertion of incorrect amino acids at those positions might destabilize a helix, thus
increasing the likelihood that the affected helix and its neighbors will refold into a beta-sheet
conformation. Conversely, Hermann Schätzl in my laboratory finds that the harmless differences
distinguishing the PrP gene of humans from those of apes and monkeys affect amino acids lying
outside of the proposed helical domains-where the divergent amino acids probably would not
profoundly influence the stability of the helical regions.
Treatment Ideas Emerge
No one knows exactly how propagation of scrapie PrP damages cells. In cell cultures, the conversion
of normal PrP to the scrapie form occurs inside neurons, after which scrapie PrP accumulates in
intracellular vesicles known as lysosomes. In the brain, filled lysosomes could conceivably burst
and damage cells. As the diseased cells died, creating holes in the brain, their prions would be
released to attack other cells.
We do know with certainty that cleavage of scrapie PrP is what produces PrP fragments that
accumulate as plaques in the brains of some patients. Those aggregates resemble plaques seen in
Alzheimer's disease, although the Alzheimer's clumps consist of a different protein. The PrP
plaques are a useful sign of prion infection, but they seem not to be a major cause of impairment.
In many people and animals with prion disease, the plaques do not arise at all.
Even though we do not yet know much about how PrP scrapie harms brain tissue, we can foresee that an
understanding of the three-dimensional structure of the PrP protein will lead to therapies. If, for
example, the four-helix-bundle model of PrP is correct , drug developers might be able to design a
compound that would bind to a central pocket that could be formed by the four helices. So bound,
the drug would stabilize these helices and prevent their conversion into beta sheets.
Another idea for therapy is inspired by research in which Weissmann and his colleagues applied
gene-targeting technology to create mice that lacked the PrP gene and so could not make PrP. By
knocking out a gene and noting the consequences of its loss, one can often deduce the usual
functions of the gene's protein product. In this case, however, the animals missing PrP displayed
no detectable abnormalities. If it turns out that PrP is truly inessential, then physicians might
one day consider delivering so-called antisense or antigene therapies to the brains of patients
with prion diseases. Such therapies aim to block genes from giving rise to unwanted proteins and
could potentially shut down production of cellular PrP [see "The New Genetic Medicines," by Jack S.
Cohen and Michael E. Hogan; SCIENTIFIC AMERICAN, December 1994]. They would thereby block PrP from
It is worth noting that the knockout mice provided a welcomed opportunity to challenge the prion
hypothesis. If the animals became ill after inoculation with prions, their sickness would have
indicated that prions could multiply even in the absence of a p re-existing pool of PrP molecules.
As I expected, inoculation with prions did not produce scrapie, and no evidence of prion replication
could be detected.
The enigma of how scrapie PrP multiplies and causes disease is not the only puzzle starting to be
solved. Another long-standing question-the mystery of how prions consisting of a single kind of
protein can vary markedly in their effects-is beginning to be answered as well. Iain H. Pattison of
the Agriculture Research Council in Compton, England, initially called attention to this phenomenon.
Years ago he obtained prions from two separate sets of goats. One isolate made inoculated animals
drowsy, whereas the second made them hyperactive. Similarly, it is now evident that some prions
cause disease quickly, whereas others do so slowly.
The Mystery of "Strains"
Alan G. Dickinson, Hugh Fraser and Moira E. Bruce of the Institute for Animal Health in Edinburgh,
who have examined the differential effects of varied isolates in mice, are among those who note that
only pathogens containing nucleic acids are known to occur in multiple strains. Hence, they and
others assert, the existence of prion "strains" indicates the prion hypothesis must be incorrect;
viruses must be at the root of scrapie and its relatives. Yet because efforts to find viral nucleic
acids have been unrewarding, the explanation for the differences must lie elsewhere.
One possibility is that prions can adopt multiple conformations. Folded in one way, a prion might
convert normal PrP to the scrapie form highly efficiently, giving rise to short incubation times.
Folded another way, it might work less efficiently. Similarly, one "conformer" might be attracted to
neuronal populations in one part of the brain, whereas another might be attracted to neurons
elsewhere, thus producing different symptoms. Considering that PrP can fold in at least two ways,
it would not be surprising to find it can collapse into other structures as well.
Since the mid-1980s we have also sought insight into a phenomenon known as the species barrier.
This concept refers to the fact that something makes it difficult for prions made by one species to
cause disease in animals of another species. The cause of this difficulty is of considerable
interest today because of the epidemic of mad cow disease in Britain. We and others have been
trying to find out whether the species barrier is strong enough to prevent the spread of prion
disease from cows to humans.
Breaking the Barrier
The barrier was discovered by Pattison, who in the 1960s found it hard to transmit scrapie between
sheep and rodents. To determine the cause of the trouble, my colleague Michael R. Scott and I later
generated transgenic mice expressing the PrP gene of the Syrian hamster-that is, making the hamster
PrP protein. The mouse gene differs from that of the hamster gene at 16 codons out of 254. Normal
mice inoculated with hamster prions rarely acquire scrapie, but the transgenic mice became ill
within about two months.
We thus concluded that we had broken the species barrier by inserting the hamster genes into the
mice. Moreover, on the basis of this and other experiments, we realized that the barrier resides in
the amino acid sequence of PrP: the more the sequence of a scrapie PrP molecule resembles the PrP
sequence of its host, the more likely it is that the host will acquire prion disease. In one of
those other experiments, for example, we examined transgenic mice carrying the Syrian hamster PrP
gene in addition to t heir own mouse gene. Those mice make normal forms of both hamster and mouse
PrP. When we inoculated the animals with mouse prions, they made more mouse prions. When we
inoculated them with hamster prions, they made hamster prions. From this behavior, we learned that
prions preferentially interact with cellular PrP of homologous, or like, composition.
The attraction of scrapie PrP for cellular PrP having the same sequence probably explains why
scrapie managed to spread to cows in England from food consisting of sheep tissue: sheep and bovine
PrP differ only at seven positions. In contrast, the sequence difference between human and bovine
PrP is large: the molecules diverge at more than 30 positions. Because the variance is great, the
likelihood of transmission from cows to people would seem to be low. Consistent with this
assessment are epidemiological studies by W. Bryan Matthews, a professor emeritus at the University
of Oxford. Matthews found no link between scrapie in sheep and the occurrence of Creutzfeldt-Jakob
disease in sheep-farming countries.
On the other hand, two farmers who had "mad cows" in their herds have recently died of
Creutzfeldt-Jakob disease. Their deaths may have nothing to do with the bovine epidemic, but the
situation bears watching. It may turn out that certain parts of the PrP molecule are more important
than others for breaking the species barrier. If that is the case, and if cow PrP closely resembles
human PrP in the critical regions, then the likelihood of danger might turn out to be higher than a
simple comparison of the complete amino acid sequences would suggest.
We began to consider the possibility that some parts of the PrP molecule might be particularly
important to the species barrier after a study related to this blockade took an odd turn. My
colleague Glenn C. Telling had created transgenic mice carrying a hybrid PrP gene that consisted of
human codes flanked on either side by mouse codes; this gene gave rise to a hybrid protein. Then he
introduced brain tissue from patients who had died of Creutzfeldt-Jakob disease or
Gerstmann-Sträussler-Scheinker disease into the transgenic animals. Oddly enough, the animals
became ill much more frequently and faster than did mice carrying a full human PrP gene, which
diverges from mouse PrP at 28 positions. This outcome implied that similarity in the central region
of the PrP molecule may be more critical than it is in the other segments.
The result also lent support to earlier indications-uncovered by Shu-Lian Yang in DeArmond's
laboratory and Albert Taraboulos in my group-that molecules made by the host can influence the
behavior of scrapie PrP. We speculate that in the hybrid-gene study, a mouse protein, possibly a
"chaperone" normally involved in folding nascent protein chains, recognized one of the two
mouse-derived regions of the hybrid PrP protein. This chaperone bound to that region and helped to
refold the hybrid molecule into the scrapie conformation. The chaperone did not provide similar
help in mice making a totally human PrP protein, presumably because the human protein lacked a
binding site for the mouse factor.
The List May Grow
An unforeseen story has recently emerged from studies of transgenic mice making unusually high
amounts of normal PrP proteins. DeArmond, David Westaway in our group and George A. Carlson of the
McLaughlin Laboratory in Great Falls, Mont., became perplexed when they noted that some older
transgenic mice developed an illness characterized by rigidity and diminished grooming. When we
pursued the cause, we found that making excessive amounts of PrP can eventually lead to
neurodegeneration and, surprisingly, to destruction of both muscles and peripheral nerves. These
discoveries widen the spectrum of prion diseases and are prompting a search for human prion diseases
that affect the peripheral nervous system and muscles.
Investigations of animals that overproduce PrP have yielded another benefit as well. They offer a
clue as to how the sporadic form of Creutzfeldt-Jakob disease might arise. For a time I suspected
that sporadic disease might begin when the wear and tear of living led to a mutation of the PrP gene
in at least one cell in the body. Eventually, the mutated protein might switch to the scrapie form
and gradually propagate itself, until the buildup of scrapie PrP crossed the threshold to overt
disease. The mouse studies suggest that at some point in the lives of the one in a million
individuals who acquire sporadic Creutzfeldt-Jakob disease, cellular PrP may spontaneously convert
to the scrapie form. The experiments also raise the possibility that people who become affected
with sporadic Creutzfeldt-Jakob disease overproduce PrP, but we do not yet know if, in fact, they
All the known prion diseases in humans have now been modeled in mice. With our most recent work we
have inadvertently developed an animal model for sporadic prion disease. Mice inoculated with brain
extracts from scrapie-infected animals and from humans afflicted with Creutzfeldt-Jakob disease
have long provided a model for the infectious forms of prion disorders. And the inherited prion
diseases have been modeled in transgenic mice carrying mutant PrP genes. These murine
representations of the human prion afflictions should not only extend understanding of how prions
cause brain degeneration, they should also create opportunities to evaluate therapies for these
Ongoing research may also help determine whether prions consisting of other proteins play a part in
more common neurodegenerative conditions, including Alzheimer's disease, Parkinson's disease and
amyotrophic lateral sclerosis. There are some marked similarities in all these disorders. As is
true of the known prion diseases, the more widespread ills mostly occur sporadically but sometimes
"run" in families. All are also usually diseases of middle to later life and are marked by similar
pathology: neurons degenerate, protein deposits can accumulate as plaques, and glial cells (which
support and nourish nerve cells) grow larger in reaction to damage to neurons. Strikingly, in none
of these disorders do white blood cells-those ever present warriors of the immune system-infiltrate
the brain. If a virus were involved in these illnesses, white cells would be expected to appear.
Recent findings in yeast encourage speculation that prions unrelated in amino acid sequence to the
PrP protein could exist. Reed B. Wickner of the NIH reports that a protein called Ure2p might
sometimes change its conformation, thereby affecting its activity in the cell. In one shape, the
protein is active; in the other, it is silent.
The collected studies described here argue persuasively that the prion is an entirely new class of
infectious pathogen and that prion diseases result from aberrations of protein conformation.
Whether changes in protein shape are responsible for common neurodegenerative diseases, such as
Alzheimer's, remains unknown, but it is a possibility that should not be ignored.
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