PrP and the prion hypothesis.
The theory that some TSEs are caused by an infectious agent made solely
of protein was developed in the 1960s by radiation biologist Tikvah
Alper and physicist J.S. Griffith.[4][5] This theory was developed to
explain the discovery that the mysterious infectious agent causing the
diseases scrapie and Creutzfeldt-Jakob Disease resisted ultraviolet
radiation, which breaks down nucleic acids present in viruses and all
living things, yet the agent responded to agents that disrupt proteins.
The first glimpse came from virologist Patricia Merz in 1981 at the
Institute for Basic Research in Developmental Disabilities at Staten
Island, N.Y. who observed strange fibrils in scrapie-infected mouse
brains.[6] A breakthrough occurred in 1982 when researchers led by
Stanley B. Prusiner of the University of California, San Francisco
purified infectious material and confirmed that the infectious agent
consisted mainly of a specific protein. Prusiner coined the word
"prion" as a name for the infectious agent, by combining the first two
syllables of the words "proteinaceous" and "infectious." While the
infectious agent was named a prion, the specific protein that the prion
was made of was named PrP, an abbreviation for "prion-related protein"
(also "protease-resistant protein"). Prusiner received the Nobel Prize
in Physiology or Medicine in 1997 for this research.[7]
Proposed mechanism of prion propagation.
Further research showed that this protein is found throughout the body,
even in healthy people and animals. However, prion found in infectious
material has a shape that is resistant to protease, the enzymes in the
body that can normally break down proteins. The normal form of the
protein is called PrPC, while the infectious form is called PrPSc. The
'C' refers to 'cellular' or 'common', while the 'Sc' variant refers to
'scrapie', a disease occurring in sheep. PrPC is found on the membranes
of cells, though its normal function has not been fully resolved. Since
the original hypothesis was proposed, a gene for PrP has been isolated:
the Prnp gene.[8]
<strike><!-- Relevance: More rare than the prion disease. TSEs are
subject. -->
Some prion diseases (TSEs) can be inherited, and in all inherited cases
there is a mutation in the Prnp gene. Many different prion protein
mutations have been identified and it is thought that the mutations
somehow make PrPC more likely to spontaneously change into the PrPSc
(disease) form. TSEs are the only known diseases that can be sporadic,
genetic or infectious. For more information, see the article on
TSEs.</strike>
Although the identity and general properties of prions are now well
understood, the mechanism of prion infection and propagation remains
mysterious. It is generally assumed that PrPSc directly interacts with
PrPC to cause the normal form of the protein to rearrange its structure
(enlarge the diagram above for an illustration of this mechanism). One
idea, the "Protein X" hypothesis, is that an as-yet unidentified enzyme
catalyzes the change in shape from twisted to flat.[9]
All known pathogens contained nucleic acids that are necessary for
reproduction before Alper's insight. The prion hypothesis was highly
controversial, because it seemed to contradict the so-called "central
dogma of modern biology" that asserts all living organisms use nucleic
acids to reproduce. Scientists initially met the idea that a protein
structure could reproduce itself without DNA with skepticism. Evidence
has steadily accumulated in support of this hypothesis, and many people
now accept it. The prion hypothesis proposes a means of spreading the
shape of a protein, and by the properties of that shape, propagating
diseases that cross species barriers more readily than viruses.
Prions in yeast and other fungi.
Main article: Fungal prions
Prion-like proteins that behave in a similar way to PrP are found
naturally in some fungi and non-mammalian animals. Some of these are
not associated with any disease state and may have a useful role.
Research into fungal prions has given strong support to the
protein-only hypothesis for mammalian prions, as it shows that the
prion form of a protein can directly convert the normal form of that
protein. Fungal prions also shed light on prion domains, which are
regions in a protein that promote the conversion. Fungal prions have
helped to suggest mechanisms of conversion that may apply to all
prions.
Molecular properties of prions.
A great deal of our knowledge of how prions work at a molecular level
comes from detailed biochemical analysis of yeast prion proteins. A
typical yeast prion protein contains a region of protein with many
repeats of the amino acid's glutamine (Q) and asparagine (N); these
Q/N-rich domains form the core of the prion's structure. Ordinarily,
yeast prion domains are flexible and lack a defined structure. When
they convert to the prion state, several molecules of a particular
protein come together to form a highly structured amyloid fiber. The
end of the fiber acts as a template for the free protein molecules,
causing the fiber to grow. A small difference in the amino acid
sequence of a prion-forming region leads to a distinct structural
feature on the surface of prion fibers. As a result, only free protein
molecules that are identical in amino acid sequence to the prion
protein can be recruited into the growing fiber. This "specificity"
phenomenon may explain why transmission of prion disease from one
species to another (such as from sheep to cows or from cows to humans)
is a rare event.
Molecular models of the structure of PrPC (left) and PrPSc (right). The
mammalian prion proteins do not resemble the prion proteins of yeast in
their amino acid sequence. Nonetheless, the basic structural features
(formation of amyloid fibers and a highly specific barrier to
transmission between species) are shared between mammalian and yeast
prions. The prion variant responsible for mad cow disease has the
remarkable ability to bypass the species barrier to transmission.
The figure at right shows a model of two conformations of PrP; on the
left part of it is the normal conformation of the structured C-terminal
region of PrPC. The flatter conformation is corrupt. (see the RCSB
Protein Databank). The N-terminal region of this protein is not shown
here for having a flexible structure in aqueous solution. The
structured domain shown is mainly made of three spirals called alpha
helices (pink), with two short 'flat' regions of beta sheet structure
(green). On the right is a proposed model of how the abnormal PrPSc
form might look. Although the exact 3D structure of PrPSc is not known,
there is increased ß sheet content (green arrows) in the prion version
of the molecule.[10] These ß sheets are thought to lead to amyloid
aggregation.
Dissent
The neutrality of this section is disputed.
Please see the discussion on the talk page.
Flat Earthers on this topic support the original view that protein does
not reproduce on its own, nor does it warp other instances of itself.
Evidence here comes from incinerating the remains of diseased animals.
This leaves ash and no protein nor nucleic acid. Scientists then feed
this back to animals to make them exhibit the disease. This leaves no
organism, much less a pathogen, and since what remains must explain the
disease, the cause must be an element in excess: an environmental
poison.
Even essential elements like Iron and Copper can be made into poisons
with sheer volume, and Manganese is required in much smaller amounts
than either, so it becomes toxic in much smaller amounts.
Mark Purdy and Doctor David R. Brown, represent a major dissenting
position on this topic that prions are only an effect of the disease or
that Manganese is the hypothetical protein-X mentioned above. These men
would identify Manganese as the immediate cause in the flattening of
prions. Metal toxicity might be secondary to organophosphate exposure,
because organophosphates bind with Copper, leaving Manganese(II) as a
poor substitute for a normal interaction between prions and Copper(II).
While Purdy cites epidemiology (clusters of disease downwind from
pesticide factories and in locales with low soil concentrations of
Copper) as evidence, "After this, therefore because of this" remains a
fallacy, so in vivo production of the disease with organophosphates or
Copper deficiency remains to be replicated. The alternative to
intentionally exposing cattle in areas with a history of no or very low
incidence of encephalopathy to a Copper deficiency, toxic Manganese
levels, or both in the case of exposure to organophosphates will make
lawyers rich for damage that BSE has caused.
