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For the bird called a "prion", see Prion (bird)
Prions - short for proteinaceous infectious particle - are infectious self-reproducing protein structures. Though their exact mechanisms of action and reproduction are still
unknown, it is now commonly accepted that they are responsible for a number of previously known but little-understood diseases
generally classified under transmissible spongiform encephalopathy (TSEs) diseases, including scrapie (a disease of sheep), kuru
(found in members of the cannibalistic Fore tribe in Papua New Guinea), and bovine spongiform encephalopathy ("mad cow disease"). These diseases affect the
structure of brain tissue and are all fatal and untreatable.
Prions were first hypothesized in 1982 by Stanley B. Prusiner of UCSF, who was awarded the Nobel Prize in physiology or
medicine in 1997 for the discovery. Prusiner formed the word "prion" from a combination
of the words "proteinaceous infectious particle".
Overview
Prior to Prusiner's insight, all known pathogens (bacteria, viruses, etc.) contained nucleic acids, which enable reproduction. The prion hypothesis was developed to
explain why the mysterious infectious agent causing Creutzfeldt-Jakob disease resisted ultraviolet radiation (which breaks down nucleic acids) but
responded to agents that disrupt proteins. This hypothesis was originally highly controversial, because it seemed to contradict
the "central dogma of modern biology," which asserts that all living organisms use DNA to reproduce. Prusiner's idea that a
protein containing no DNA could reproduce itself was initially met with skepticism, but evidence has steadily accumulated in
support of the hypothesis, and it is now widely accepted. Rather than contradicting the central role of DNA, however, the prion
hypothesis suggests a special and possibly exceptional case in which merely changing the shape of a protein (without
changing its amino acid sequence) can alter its biological properties.
A breakthrough occurred when researchers discovered that the infectious agent consisted mainly of a specific protein, which
Prusiner called PrP (an abbreviation for "prion protein"). This protein is found in the membranes of normal cells (its precise function
is not known), but an altered shape distinguished the infectious agent. The normal one is called PrPC, while the
infectious one is called PrPSC (the 'C' refers to 'cellular' PrP, while the 'SC' refers to 'scrapie', a prion disease occurring in sheep). It is hypothesized that the distorted protein somehow induces
normal PrP to also become distorted, producing a chain reaction that
both propagates the disease and generates new infectious material. Since the original hypothesis was proposed, a gene for the PrP protein has been isolated, the mutation that causes the variant shape has been identified and successfully cloned, and studies using genetically
altered mice have bolstered the prion hypothesis. The evidence in support of the hypothesis is quite strong now, but not
incontrovertible.
In Prusiner's second Scientific American article, he proposed a mechanism for prion propagation that does not require
direct action of a prion protein on a normal protein. The suggestion there is that both N, the normal protein, and P, the prion
protein, are a product of a post-translational metabolic pathway
that forks, leading to either N or P. The presence of P has a negative feedback
effect on the fork yielding N, so that P causes less and less N to be made, and more and more P. (For the Creutzfeld-Jakob prion
PrP, N corresponds to PrPC, and P corresponds to PrPSC.)
Prions appear to be most infectious when in direct contact with affected tissues. For example, Creutzfeldt-Jakob disease has
been transmitted to patients taking injections of growth hormone
harvested from human pituitary glands, and from instruments used for
brain surgery (prions can
survive the "autoclave" sterilization process used for most surgical
instruments). It is also believed that dietary consumption of affected animals can cause prions to accumulate slowly, especially
when cannibalism or similar practices allow the proteins to accumulate over
more than one generation. Laws in developed countries now proscribe the use of rendered ruminant proteins in ruminant feed as a precaution against
the spread of prion infection in cattle and other ruminants.
The reason prions are not detected by the immune system is that their
"safe" form is already present from birth in the body. The only distinction the "dangerous" prions have is that they are folded
slightly differently. Prions infect the nerve lining of neural cells, forming an aggregate which ultimately destroys nerve cells. Depending on the area of the brain which they infect the symptoms can be
different. For example, infecting the cerebellum causes impairment of movement.
Infecting the cerebral cortex results in a decrease in memory and
mental agility.
Useful prions
Not all prions are dangerous; in fact they are found naturally in many (perhaps all) plants and animals. Because of this,
scientists reasoned that the deformed proteins must give some sort of evolutionary advantage to their host. This was proved to be
the case when studying a specific type of moss covering forest floors. Normally viruses can
travel from an infected moss section to an uninfected moss section when the areas grow close enough for the outer cells to touch.
However prions were discovered in the infected moss, which appeared to travel part way into the sides of the uninfected moss.
This caused cells on the edges of the moss to die, creating a barrier of dead cells which viruses are unable to cross, preventing
contamination.
Since 1965, researchers working with the yeast
Saccharomyces cerevisiae under the
guidance of Brian Cox had been characterizing a strange form of inheritance, which they referred to as the [PSI+] element. In
1994, Reed Wickner proposed that [PSI+] and another heritable element were both prions. It was soon noticed that
heat shock proteins (which help other proteins fold properly)
were able to reduce the effects of [PSI+]. Researchers studied how the amino acid sequence contributed to the ability of the PSI
protein (Sup35p) to convert between its prion and non-prion state. This research led Susan Lindquist to propose that prionic conversion might be advantageous in some situations, leading to
their evolutionary conservation.
Another way of looking at the definition of a prion may be to call them as an 'auto-chaperone' protein. Chaperones are proteins that help fold other proteins into their functional
conformations. Thus they can be considered as specific cases of more generic mechanisms of protein interactions.
As of 2003, the following additional proteins in Saccharomyces cerevisiae had
been identified or postulated as prions:
- Rnq1p, forming the [ RNQ ] element;
- Ure2p, forming the [ URE3 ] element;
- New1p, forming the [ NU ] element.
Prions have also been speculatively linked to memory [1]
, heterokaryon incompatibility, [2]
and cellular differentiation, the process by which
stem cells take on specialized functions (such as muscle or blood cells).
The prion protein
Many (if not all) known prion proteins contain N-terminal domains rich in glutamine with predicted conformational flexibility.
This domain is necessary and sufficient to enable the protein to enter the prion state.
Other prion diseases
See also
External links
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