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A neurologist has presented some novel ideas on the cause of some
neurological disorders. These thoughts were published in the August 1996
edition of Scientific American Magazine.
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The Prion Diseases
Prions, once dismissed as an impossibility, have now gained wide
recognition as extraordinary agents that cause a number of
infectious, genetic and spontaneous disorders
by Stanley B. Prusiner
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 the 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
replication.
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 to 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. AfBicted 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 aUeicted 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. Iatrogenic
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-Str...ussler-Scheinker disease (which is
manifest as ataxia and other signs of damage to the
cerebellum) and fatal familial insomnia (in which
dementia follows diUculty 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.
Amazing Discovery
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 because, 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,
nonthreatening 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 scrapielike 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 scrapielike 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-Str...ussler-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 102,
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-Str...ussler-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
56 and 57].
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-Str...ussler-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 DYesseldorf)
has produced no evidence that such genetic material is
attached to prions.
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 interior.
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 Sch...tzel 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 inBuence 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 propagating itself.
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 preexisting 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 eUciently, giving
rise to short incubation times. Folded another way, it
might work less eUciently. 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 diUcult for
prions made by one species to cause disease in animals
of another species. The cause of this diUculty 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 their 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 Banked 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-Str...ussler-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 inBuence 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 aUeicted with sporadic Creutzfeldt-Jakob
disease overproduce PrP, but we do not yet know if, in
fact, they do.
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 aUeictions should not
only extend understanding of how prions cause brain
degeneration, they should also create opportunities to
evaluate therapies for these devastating maladies.
Striking Similarities
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.
FURTHER READING
Scrapie Disease In Sheep. Herbert B. Parry. Edited by
D. R. Oppenheimer. Academic Press, 1983.
Molecular Biology Of Prion Diseases. S. B. Prusiner
in "Science," Vol. 252, pages 1515-1522; June 14,
1991.
Prion Diseases Of Humans And Animals. Edited by
S. B. Prusiner, J. Collinge, J. Powell and B. Anderton.
Ellis Horwood, 1992.
Fatal Familial Insomnia: Inherited Prion Diseases,
Sleep, And The Thalamus. Edited by C. Guilleminault
et al. Raven Press, 1994.
Molecular Biology Of Prion Diseases. Special issue of
"Philosophical Transactions of the Royal Society of
London, Series B," Vol. 343, No. 1306; March 29,
1994.
Structural Clues To Prion Replication. F. E. Cohen,
K.-M. Pan, Z. Huang, M. Baldwin, R. J. Fletterick and
S. B. Prusiner in "Science," Vol. 264, pages 530-531;
April 22, 1994.
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to [log in to unmask] with Archive Search as the subject.
LibraryH Searches of the Subject: line, From: line and Body are
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