form may appear either "spontaneously" without a mutation in the
sequence of the normal protein, or as a result
of a mutation in the sequence of the normal protein.
However, the rare
form has the strange property of being able to cause the normal form to change
conformation to that of the rare form, so it becomes another
Any property associated with the rare form, which distinguishes it from the normal form,
is then acquired by what had been the normal form. These properties include
(i) causing more molecules of the normal form to change
conformation to the rare form (i.e. each changed molecule recruits
further molecules, which, in turn, recruit further molecules in
an exponential manner),
- (ii) a loss in solubility resulting in aggregation, and
- (iii) resistance to proteases (which
originally led to the idea that prions might not be proteins; hence " proteinaceous")
is an important protein property. As their limit of solubility is approached, molecules of
a a particular protein species will tend to aggregate. This aggregation is usually
correlated with a loss of function. The aggregation is protein-specific, in that proteins
tend to aggregate like-with-like,
leaving other protein species (of greater solubility) still
This property has long been exploited by biochemists to purify different
protein species from mixtures by differential precipitation.
Indeed, experimentally it can be shown that in a cytosol containing more than one
potential prion-precursor species, seeding with a few prion molecules of one species causes conversion and
aggregation only of the
corresponding normal species. The other species remains soluble (Santoso et al.
one molecule of prion protein in a cell can act as a "seed",
catalysing the formation of a prion aggregate. The crowded cytosol can be viewed as poised
on the verge of concentration "criticality", much
as a lake at sub-zero temperatures may need the addition of just one ice crystal to make
the entire lake freeze (Fulton, 1982; Forsdyke
1995). The unremitting activity of
molecular chaperones, which include member of the heat-shock protein family, can usually
ensure that protein conformations are kept in soluble mode, so that the criticality
threshold is not crossed (e.g. Warwick et al.
we come to the "infectious" aspect of the name.
Proteins with the prion property have been identified both in unicellular microorganisms (yeast) and organisms considered higher on the evolutionary scale.
Prions transferred from individual to individual, either within a species, or between
different species, can sometimes get into cells and convert (and so
decrease the solubility of) the corresponding normal resident
proteins, to the detriment of the organism.
infection may be inherited, or acquired. As far as we know, normal yeast either do not
contain the abnormal prion forms or can deal with them before the exponential
self-aggregation process can start (i.e. a role for molecular
chaperones). When yeast cells divide, cytoplasmic contents are passed to daughter
cells, so that, if the exponential process has started for some reason, any resulting
change in phenotype is inherited cytoplasmically.
far as we know, humans do not pass prion proteins cytoplasmically in the germ line.
However, a disease of cannibals in New Guinea (Kuru)
found to be caused by ingested prion protein being able to resist degradation by
intestinal proteases. In this respect the acquired protein was "infectious"
in that it was, like a bacterium, the agent transferring the disease from person to
some cases, the infection crosses species lines. Thus, on ingesting prion-containing meat,
humans can acquire "mad cow's disease". Kuru and
mad cow's disease are members of a group of diseases (not all of
which are prion-based), in which neurological disfunction is associated with
protein aggregation in nerve tissue.
prion phenomenon reveals a process by which a normal resident
protein species ("self") can serve as a recognition device for an extrinsic
protein ("not self") with
which it shares some property. The recognition takes the form
of intracellular aggregation with, in the case of prion diseases, adverse consequences for
the organism. However, in principle, the phenomenon
might be turned to the advantage of the organism.
aggregation of resident molecules can be seen as creating and amplifying a signal that a specific "non-self" protein is present, thus constituting a form of
intracellular self/not-self discrimination. As a result of this recognition event, there might be a "call to arms"
such that the cell (and/or the organism) mounts a
response which is adaptively advantageous. Thus, in the words of Lindquist (1997),
prions may not be just "oddities in a biological freak show,
but actors in a larger production now playing in a theatre near you".
is an analogy here with the extracellular recognition of a not-self protein ("antigen") by a resident protein ("antibody").
In this case, the resident protein has evolved for this specific purpose and, as far as we
are aware, has no other purpose. In the case of intracellular proteins there appear to be
no dedicated molecular species of an antibody nature. Thus proteins
with some regular function in the economy of the cells may, when the conditions are
appropriate, be coopted for the aggregation function. This
aggregation (registering a protein as not-self) would then trigger various alarms, which would lead to responses advantageous
to the organism (e.g. the interferon response, upregulation of MHC
protein expression, etc.). The challenge is to try to figure how this might have
come about, how it might be manifest in known phenomena, and how models for the process
can be tested.
The Ultimate Frame of Reference in Biological
Note that the term "danger"
is currently popular among
immunologists (and it is therefore politically correct to use
it in your grant applications or controversial publications).
"Danger" or "dangerous" are attributes that inform
us that something is potentially harmful.
first a signal is recognized as emanating from a source different from
"self." This, initial
may, in itself, prompt a response. For example, if sheep grazing in
a meadow hear a sound in the wood they may move away from the wood as
a precaution. They know the sound is not from one of themselves.
However, once this primary not-self decision is made, another binary
- not-dangerous or dangerous?
If not dangerous then the source is potentially
friendly. If dangerous then the source is potentially unfriendly. So
the source is appropriately registered as:
For example, if not-self displays the attribute
"shepherd" (= friend) then the sheep relax. If not-self
displays the attribute "wolf" (= foe) then alarms sound
(bleating and running). It is true that a deaf sheep may only respond
when it sees its neighbours moving. It responds, not to not-self, not
to danger, but to the alarm. For the sheep collective, however, the
primary event is that of self/not-self discrimination.
As far as bodily systems are concerned,
is a foe and dangerous (potentially harmful), while internal "self" is
a friend and not-dangerous. Fortunately, the initial
self/not-self decision usually suffices to trigger a response (alarm).
Thus, attenuated or dead bacteria are sufficient to
immunize. Danger, per se, does not come into the picture. Bacteria are
not allowed to wander around the body, like tourists. We recognize them
as "not-self," not as dangerous.
And we do not require
them to "break windows" (manifest their potential for harm) before we respond.
When what may be deemed as "self"
becomes harmful, then some body component has begun to manifest not-self
attributes. The yard-stick for measuring the degree of potential for
harm (dangerousness), is the
degree of conversion to not-self, not the amount of damage that
has already been caused. Thus, "self"
is the ultimate frame of reference in a biological system.
Self is that which is encoded in your genes at the time of your first
appearance on this planet. Genes which change during your life so that different gene
products are synthesized may either register as still "self"
(e.g. antibody variable region genes), or
register as having transformed to "not-self" (e.g. a potential
oncogene). This may require very fine discrimination
between "self" and "near-self",
so that the
latter becomes registered as "not-self."
Forsdyke, D. R. (1995) Entropy-driven protein self-aggregation as
the basis for self/not-self discrimination in the crowded cytosol.
J. Biol. Sys. 3, 273-287.
Fulton, A. (1982) How crowded is the cytoplasm? Cell
Lindquist, S. (1997) Mad cows meet Psi-chotic yeast: the expansion of the
prion hypothesis. Cell 89, 495-498.
Prusiner, S. B. (1997) Prion diseases and the BSE crisis. Science 278, 245-251.
Santoso, A., Chien, P., Osherovich, L.Z. & Weissman, J. S. (2000) Molecular
basis of a yeast prion species barrier. Cell
Warrick, J. M., Chan, H.Y.E., Gray-Board, G. L., Chai, Y., Paulson, H.L. &
Bonini, N. (1999) Suppression of polyglutamine-mediated neurodegeneration in Drosophila
by the molecular chaperone HSP70. Nature Genetics
What Can We Do?
A major factor in the spread of the prion diseases is the
use of the by-products (offal) of one animal to feed another. Government regulations have
been drawn up to prevent this, but according to the US Office of Food and Drug
Blakeslee reports in the New York Times 11th Jan 2001):
numbers of companies involved in manufacturing animal feed are not complying with regulations meant to prevent the emergence and
spread of mad cow disease in the United States."
regulations state that feed manufacturers and companies that render slaughtered animals
into useful products generally may not feed mammals to cud-chewing animals, or ruminants,
which can carry mad cow disease.
All products that contain rendered cattle or sheep must have a label that says, "Do
not feed to ruminants," Dr. Sundlof said. Manufacturers must also have a system to
prevent ruminant products from being commingled with other rendered material like that
from chicken, fish or pork. Finally, all companies must keep records of where their
products originated and where they were sold."
180 large companies that render cattle and another ruminant, sheep, nearly a quarter were not properly labeling their products and did not have a system to prevent commingling, the F.D.A. said. And among
347 F.D.A.-licensed feed mills that handle ruminant materials ... 20 percent were not using labels with the required caution statement, and 25 percent
did not have a system to prevent
there are some 6,000 to 8,000 feed mills so small they do not require F.D.A. licenses.
They are nonetheless subject to the regulations, and of 1,593 small feed producers that
handle ruminant material and have been inspected, 40 percent were not using approved labels and 25 percent had no system in place to prevent commingling."