Associated with numerous neurological diseases, misfolded proteins may also play decisive roles in normal cellular functioning.
In Kurt Vonnegut’s Cat’s Cradle,
scientists create a highly stable form of crystalline water called
“ice-nine” that stays frozen even at high temperatures. Ice-nine
instantly freezes any liquid water it touches. Its accidental release
into nature solidifies the oceans and all contiguous bodies of water,
and global catastrophe threatens our existence. Luckily for us, ice-nine
is fictitious. But its biological counterpart, unfortunately, is not.
The misfolded proteins known as prions are very real.
Prions are proteinaceous infectious particles, formed when normal
proteins misfold and clump together. Biochemists Byron Caughey of the
National Institute of Allergy and Infectious Diseases and Peter Lansbury
of Brigham and Women’s Hospital were among the first to explore the
analogy between Vonnegut’s ice-nine and prions in their 1995 review of
scrapie, an infectious and deadly neurological disease of sheep.
1
Like ice-nine, the particles that spread scrapie consist of highly
stable crystals of a normally innocuous material found in the brains of
sheep. Crystalline clumps of a misfolded version of this protein coax
other molecules of the same protein to fold into the aberrant
conformation. The process continues until virtually all of that protein
in a cell or tissue has been converted to prions. In the case of scrapie
and other mammalian prion diseases, the consequence of this
self-amplifying cycle is an accumulation of toxic clumps of proteins
that destroys neurons and invariably kills the organism.
The chilling similarity between the modus operandi of ice-nine and
prions is an apt illustration of the long-standing and well-deserved
reputation of prions as catastrophic agents. Researchers are identifying
more and more cases of prion-like protein misfolding that cause
neurodegenerative diseases.
But a different side of prions is also coming to light. Many newly
discovered prions and prion-like proteins do not appear to cause disease
at all. On the contrary, some even protect against it. Still other
prions are turning out to be key players in basic biological processes.
(See
illustration.)
These discoveries are driving a new appreciation for prions as
versatile components in the machinery of life, a paradigm that has
fostered conceptual advances in fields as diverse as signal
transduction, memory formation, and evolution.
Prions as killers
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Proteins that can act in a prion-like manner are referred to as prion proteins or prion-forming proteins, whether or not they are in the prion conformation. A prion is the infectious particle itself, not the proteins that make it up. A prion particle is thought to be composed of one or more amyloid fibers or oligomers, which are themselves composed of prion proteins. |
Like other infectious particles, such as bacteria and viruses, prions
can spread from one organism to another. Oral uptake is the most common
natural form of transmission. Humans have also become infected through
blood transfusions, human hormone injections, and surgery with
contaminated instruments. Prions exhibit different variants, or strains,
each with distinct molecular features and clinical manifestations. But
what most fascinates scientists and the public alike is that, in
contrast to viruses and all living organisms, prions lack the canonical
information-storage molecules—DNA and RNA—yet are still able to copy and
transmit biological information.
The idea that proteins could act in a manner previously ascribed only
to nucleic acids was greeted with skepticism and ridicule when it was
first championed by Stanley Prusiner in 1982.
2
Even today there are those who maintain that prion diseases are
actually caused by viruses. But as often seems to be the case in
scientific discourse, what was once heretical is now dogma.
The
“protein-only” hypothesis, which posits that a string of amino acids is
sufficient for disease transmission, steadily gained acceptance and, in
the last three years, achieved irrefutable status when Jiyan Ma of Ohio
State University College of Medicine and colleagues generated bona fide
infectious particles from recombinant prion proteins.
3
How do proteins pull off this remarkable feat? Like the water molecules
in ice-nine, proteins within prion particles are arranged into a dense,
highly organized lattice. But unlike ice crystals, this lattice grows
in only one dimension—from either end—resulting in a proteinaceous
fiber. (See
illustration.)
Every protein subunit takes on the exact configuration of those it
flanks. The subunits at the ends of the fiber are exposed. Each of those
exposed surfaces acts as a sticky template that recruits the next
subunit, locking it down and contorting it into the same configuration.
That new subunit now acquires the property of the original, and the
process repeats ad infinitum.
Crystalline fibers, usually referred to as amyloids, have a long
association with disease in their own right, beginning in 1639 with the
first description of an autopsied spleen harboring white stones that
would later be recognized as amyloid.
4
Currently, amyloids are associated with more than two dozen incurable
human diseases, including Alzheimer’s and variant Creutzfeldt-Jakob
disease (the human version of mad cow disease), as well as Huntington’s,
Parkinson’s, and type 2 diabetes.
Since prions are composed of amyloids, are these amyloid diseases also,
in effect, prion diseases? Increasingly, the answer appears to be
“Yes.” An avalanche of recent discoveries has revealed that some of the
most prevalent and devastating neurodegenerative diseases, such as
Alzheimer’s, Parkinson’s, and Huntington’s, all spread throughout the
brain in a prion-like manner, involving self-templated protein
deposition.
5
Alzheimer’s and Parkinson’s diseases can even be transmitted between
laboratory animals (albeit deliberately), through the inoculation of
diseased brain samples into the brains of healthy recipients. Similar
results have emerged in animal models of Huntington’s and other
diseases.
Thus, the boundary between amyloid and prion diseases is
rapidly dissolving. The prospect that a similar process could occur in
the real world—with common dementias transmitting between individuals,
effectively becoming infectious diseases—is now under debate in the
scientific community.
Prions as agents of inheritance
PROMISCUOUS
PRIONS: Prion proteins recruit other proteins of the same sequence as
they grow into a neatly organized lattice. When a new monomer arrives,
it links to the fibril and assumes the exact shape of its neighbor.
Fibrils can ultimately cluster together to form large deposits, or
plaques, though the relevance of these clusters is not clear.
See full infographic: JPG | PDF© TAMI TOLPAThankfully,
there is also a bright side to prions. The chain reaction of protein
misfolding at the heart of prion propagation has also been harnessed by
some organisms for a variety of benefits, including the regulation of
gene expression and of the immune response.
This expanded view of prions traces its origin to a bizarre trait in the budding yeast, Saccharomyces cerevisiae,
that had puzzled geneticists for decades due to its non-Mendelian mode
of inheritance.
When cells expressing the trait, which manifests as an
enhanced ability to utilize poor nutrient sources, are mated with cells
that do not, the trait is inherited by all of the resulting
progeny, rather than the one-half expected if the trait had resulted
from a classical genetic mutation. This pattern of inheritance had only
been observed previously for genetic elements housed outside the
nucleus, such as in mitochondrial and viral genomes.
Unlike those
elements, however, this trait can also arise spontaneously in yeast. And
the phenotype it confers closely mimics that produced by an absence of
the nuclear gene called URE2. Paradoxically, URE2 must be expressed for the trait to occur in yeast cells.
In 1994, Reed Wickner of the National Institutes of Health made a key
observation: the bizarre yeast trait appeared at a higher frequency when
URE2 was overexpressed.
He further determined that the Ure2
proteins specifically, rather than the DNA and RNA molecules encoding
them, were responsible for this effect. Wickner then offered the only
explanation compatible with the seemingly incongruous results: the
information responsible for the trait’s inheritance was encoded by an
alteration in the Ure2 protein itself.
6
In other words, Ure2 forms a prion, which reproduces itself through the
conversion of other Ure2 molecules in the cytoplasm. During cell
division, the prion particles divide among daughter cells, thereby
perpetuating the trait in a non-Mendelian manner. (See
illustration.)
Wickner’s insight broadened the prion concept for the first time beyond
mammals, in which prions were first identified as the agents of mad cow
and related diseases, and beyond the idea of a singular prion protein
associated with those diseases. Moreover, yeast cells that harbored
these elements grew at comparable rates to those that did not,
suggesting that prions may not be universally pathogenic and may even
act as protein-based elements of inheritance in healthy organisms.
Since Wickner’s original discovery, scientists have exploited the
superior tractability and genetic resources of yeast to look for
additional prion-forming proteins. To date, researchers have determined
that approximately two dozen proteins can form prions in this organism.
And at least some of them appear to do so quite frequently.
At least
one-third of wild yeast isolates harbor traits that can be attributed to
prions.
7
These traits include changes in cell-cell adhesion, resistance to
antibiotics, and alterations in the way yeast cells use nutrients. Why
might yeast harbor so many of these elements? More importantly, do other
organisms also commonly harbor nonpathogenic prions?
The proteins that form prions in yeast tend to be involved in processes
that regulate the flow of genetic information in the cell, such as
transcription, RNA processing, and translation. Consequently,
alterations in these processes by prion formation affect the way that
such information is expressed, causing changes in phenotype that can
have dramatic consequences for the cell. Sometimes the changes are
beneficial.
Other times they are detrimental. In either case, prions
provide an added level of variation that may give the population a
greater chance of surviving an otherwise dooming environmental change.
In this sense, populations of yeast cells appear to be exploiting prions
as phenotypic “bet-hedging” devices, to ensure that they collectively
harbor the phenotypic diversity necessary to survive a dynamic and often
harsh environment.
Of course, with the risk that prions can turn
pathogenic, this raises the question of why cells might take such
measures for this purpose, rather than relying on common and relatively
innocuous sources of phenotypic diversity, such as genetic variation and
transcriptional “noise.”
In my own lab at the University of Texas (UT) Southwestern Medical
Center, we sought to answer this question by looking at the types of
genetic information most heavily regulated by prions. Not surprisingly,
we found that prion-forming transcription factors each target a
disparate group of genes. However, one particular yeast gene,
FLO11, had a pronounced tendency to be subject to prion regulation.
FLO11
encodes a protein involved in cell surface adhesion, functioning like
molecular Velcro to enable cells to stick to one another in various
arrangements. In effect, the Flo11p protein allows yeast cells to
temporarily abandon their normally solitary lifestyles in favor of a
more communal existence.
8
Prions may not be universally pathogenic and may even act as protein-based elements of inheritance in healthy organisms.
The benefits of Flo11p-dependent multicellularity are multifold.
8
In some cases, Flo11p allows cells to remain attached after they
divide, enabling them to collectively orient their growth toward more
hospitable environments. Other times, such as during the fermentation of
Sherry wine, yeast cells form Flo11p-dependent mats that catch their
own carbon dioxide bubbles, allowing the yeast to rise to the surface of
the grape must where oxygen is more plentiful. Importantly, all
Flo11p-dependent multicellular behaviors require the participating cells
to act in a cooperative fashion. If some cells do not produce the
adhesion protein, they risk compromising the integrity of the entire
structure. Therefore, the success of the strategy—and the fitness payoff
for adopting it—hinges on the commitment of each cell to a stable,
multigenerational developmental program.
The self-perpetuating nature of prions is an ideal way for cooperating
lineages to enforce that commitment. We found that when the
transcription factor Mot3p converts to a prion form, it activates
FLO11 (among other genes) and stably perpetuates the multicellular state in subsequent generations.
9
By virtue of their common descent and shared inheritance of the prions,
all cells in the lineage act together to achieve a common goal. Mot3p,
along with multiple other prion proteins that regulate FLO11, is tuned
to respond to environmental signals, such as changes in pH or depletion
of nutrients, and to exert unique regulatory responses. This likely
affords yeast a measure of plasticity in the way that they deploy
multicellularity, enabling lineages of cells to physically morph to fit
the unique demands of new environments.
Prions as saviors
DIVERSE
EFFECTS OF PRIONS: Prions are most well known for their role in
disease. Spongiform encephalopathies, such as mad cow disease and
scrapie in sheep, are the result of a toxic accumulation of prions in
the brains of these animals. In humans, prions have been identified as
the cause of the fatal Creutzfeldt-Jakob disease (the human version of
mad cow disease), and scientists speculate that they underlie many other
neurodegenerative disorders, including Alzheimer’s, Huntington’s, and
Parkinson’s. But studies in yeast point to a wide range of prion
activity in healthy cells, suggesting the reactive proteins may perform
functions critical to normal cellular life.
See full infographic: JPG | PDF© MEDI-MATION LTD/SCIENCE SOURCE; © RUSSELL KIGHTLEY/SCIENCE SOURCEFor
many aspects of cell biology, what has been true in yeast is often true
in higher organisms and even humans. Do human cells also take advantage
of prion switches?
The first hint that we may indeed harbor beneficial prions surfaced in
2003, when Eric Kandel and colleagues at Columbia University noticed
that a neuronal protein called cytoplasmic polyadenylation element
binding protein (CPEB) has a sequence that is remarkably reminiscent of
yeast prion proteins.
Working with an isoform of CPEB from the sea slug
Aplysia californica,
they discovered that the protein plays a key role in the formation of
long-term memories. Following a hunch, the researchers then used yeast
cells to test whether the protein could in fact form prions. It did.
10
Since then, evidence has accumulated that CPEB and functionally related
proteins may indeed behave like prions in the neurons of
Aplysia, fruit flies, and even humans.
11
These prions presumably not only perpetuate themselves, but also
localize the synthesis of important proteins to synapses in response to
neurotransmitter stimulation. In other words, neurons appear to have
co-opted the self-sustaining prion switch as a key mechanism for the
formation of memories.
Since this discovery, there have been a number of other suspected prion
proteins identified in higher organisms. The most definitive evidence
for a functional prion switch in humans was recently provided by James
Chen and colleagues here at the UT Southwestern Medical Center. Chen’s
team studies the body’s innate immune system, the ability to distinguish
self from nonself and to mount the appropriate responses to defeat
pathogens before they take hold.
In the course of their research, the
team found that one particular protein, called MAVS, which is key to our
innate ability to fight certain viral infections, acquires a
self-perpetuating fibrillar form in cells that have become infected with
virus.
12
The rapid prion-like templated conversion of MAVS amplifies the
cellular alarm signal and ultimately induces the production of
interferons that recruit macrophages and other immune factors to combat
the infection.
GROWING
FIBRILS: Prion proteins come together to form amyloid fibers (pictured
here), which themselves can cluster into prion particles.
© DUNG VO TRUNG/SYGMA/CORBISHere,
a prion-based molecular switch may be exactly what the situation calls
for. The self-sustaining and irreversible nature of prions endows MAVS
with an executive role in the immune response.
Once a virus is detected,
the cell must resolve to stop that virus from hijacking its own
machinery, even if it means signaling its own destruction in the
process. Failing to do so risks compromising the health of the entire
organism.
Other proteins in the same superfamily as MAVS also seem to
have prion-like properties.
13
And two other proteins that are not related but have similar
functions—the RIP1 and RIP3 kinases—polymerize into filamentous amyloids
that are necessary to induce programmed necrosis, a form of cellular
suicide important for normal body development. Thus, ironically, it is
now clear that the same process that causes devastating
neurodegenerative diseases also lies at the heart of our innate ability
to fend off other diseases.
Across biological systems, prions appear to determine cell fate, for
better or for worse. For some proteins in the human brain, the aberrant
formation of prions leads to an irreversible and agonizing decline in
cognitive capacity and ultimately to death. For others, prion formation
may be critical to the function of the brain itself.
Elsewhere in our
body, prion-like switches commit cells to different forms of programmed
suicide that are critical for normal development and that protect us
from infectious disease. And in yeast, prion formation appears to be
linked to one of the most significant evolutionary transitions in life’s
history—the emergence of multicellularity. Perhaps the real-life
ice-nine is not all bad after all.
Randal Halfmann is a Sara and Frank McKnight independent
postdoctoral fellow at the University of Texas Southwestern Medical
Center in Dallas.
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