THE 'protein only' hypothesis' states that a modified form of normal prion protein triggers infectious neurodegenerative diseases, such as bovine spongiform encephalopathy (BSE), or Creutzfeldt-Jakob disease (CJD) in humans.

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Prion proteins
THE 'protein only' hypothesis' states that a
modified form of normal prion protein triggers
infectious neurodegenerative diseases, such as
bovine spongiform encephalopathy (BSE), or
Creutzfeldt-Jakob disease (CJD) in humans.
Prion proteins are thought to exist in two
different conformations the 'benign' PrPc form,
and the infectious 'scrapie form', PrPSc.
Knowledge of the three-dimensional structure of
prpc is essential for understanding the
transition to PrPSc.
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Schematic representation of the
post-translational modifications (a) and
secondary structure (b) of murine PrP
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Structure of the PrPc

• 210 aminoacids
• 33 - 35 kDa
• 2 N-linked oligosaccharydes
• GPI anchor (membrane-bound)
• C-terminal 3 a-helices and 2 antiparalell
  b-sheets

Solution structure of PrPc obtained last year by
Wüthrich, Glockshuber, and coworkers at the Swiss
Federal Institute of Technology shows three -
helices and an antiparallel ß-sheet at the
protein's carboxy terminus and a "flexibly
disordered" segment at its amino terminus.
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PrP gene
MANLGCWMLVLFVATWSDLGLCKKRPKPGGWNTGGSRYPGQGSPGGNRYP
PQGGGGWGQPHGGGWGQPHGGGWGQPHGGGWGQPHGGGWGQ
GGGTHSQWNKPSKPKTNMKHMAGAAAAGAVVGGLGGYMLGSAMSRPIIHF
GSDYEDRYYRENMHRYPNQ VYYRPMDEYSNQNNFVHDCVNITIKQHTVT
TTTKGENFTETDVKMMERVVEQMCITQYERESQAYYQRGS
SMVLFSSPPVILLISFLIFLIVG
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Ribbon diagram of the structure of the mouse
prion protein domain PrP(121-231)
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Globular fold and surface properties of
PrP(121-231).
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The propagation of infectious prion protein
occurs via conversion of normal prion protein
(PrPc, left) to a disease-causing form (PrPSc,
right). In the refolding process, some of the
-helical regions (purple coils) in PrPc unfold,
forming an extended ß-sheet region (flat blue
arrows).
Transmission electron micrographs obtained by
Lindquist and coworkers of the University of
Chicago show fibers formed by yeast Sup35
protein. At right is a single fiber at higher
magnification.
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Mutations in the PrP gene
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Spongiform Encephalopathies
This is your Brain . . . . . . . this is your
Brain on Beef
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• Virus hypothesis
• The genetic information defining the properties
  of the various scrapie strains is encoded by a
  nucleic acid.
• The important role of PrP in disease might be
  explained in that PrP plays an essential role in
  the infection and spreading of the virus in the
  host.
• Mutations in PrPC would alter susceptibility to
  the disease.
• The species barrier for infection could be caused
  by a reduced affinity of a given virus to the
  PrPC molecule of a different host species.
• Conversion of PrPC into PrPSc would be brought
  about by the interaction of the virus with PrPC.
• The virus hypothesis readily explains the
  existence of distinct scrapie strains however,
  it is challenged by the claim that in
  preparations of highly enriched infectivity, the
  average size of a nucleic acid per infectious
  unit is not larger than 80 nucleotides

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• Virino hypothesis
• Postulates that the infectious particle consists
  of a small nucleic acid coated by a host protein.
  
• Variations in the nucleic acid sequence could
  account for the existence of distinct strains, as
  for example, in viroids.
• The size of the nucleic acid could be very small
  since it does not have to encode for any
  proteins.
• The unusual resistance to treatments destroying
  or modifying nucleic acids could result from a
  protective effect of the coat.
• The most likely candidate for the host protein
  forming the coat of the virino is PrPSc. Standard
  preparations of purified infectivity usually
  contain approximately 105 PrPSc molecules per
  infectious
• Infectivity might be associated to a
  subpopulation of PrPSc molecules, denominated
  PrP, which may have escaped detection because it
  is extremely rare or difficult to distinguish
  from the rest of PrPSc.

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• Protein only hypothesis
• The information for strain specificity is carried
  by an infectious protein.
• To explain the mechanism of propagation of such
  an unusual infectious agent, it was proposed that
  the agent consisted of a modified host protein
  which was able to convert the host protein into a
  likeness of itself.
• In order to account for the strain specificities,
  the modified host protein would have to exist in
  various different isoforms. The most likely
  candidate for an infectious protein causing TSEs
  is PrPSc (or PrP) because it represents a
  disease-associated posttranslational modification
  of a host-encoded protein and because of its
  alleged association with infectivity.

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Two protein only models for the molecular
mechanism refolding model - the
rate-determining step is the conformational
conversion of PrPC into PrPSc, a process which is
catalyzed by the formation of a PrPC - PrPSc
heterodimer nucleation-dependent
polymerization model the rate-determining step
is the formation of a nucleus of polymerized
PrPSc, which, once formed, promotes further
polymerization of PrPSc. Such nuclei would act as
polymerization seeds in an infected host thereby
rapidly driving host PrP into the aggregated
state.
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Microscopy of the normal brain (top left) shows
dark-staining neurons in the cerebral cortex with
no spongy change in surrounding tissue. In
classical CJD (top right), brain cortex contains
numerous small vacuoles that give a spongelike
appearance. In new-variant CJD (bottom left), the
cortex shows less severe sponginess but contains
"florid" plaques--aggregates of amloid material
surrounded by spongy change. Florid plaques in
new-variant CJD (bottom right) stain intensely
for prion protein (brown).
According to the template assistance (or
heterodimer) model, PrPc monomer adds to PrPSc
monomer to form PrPSc -PrPC heterdimer, which
rapidly converts to PrPSc homodimer. The
homodimer may then dissociate, releasing new
PrPSc monomer. The nucleated polymerization
mechanism proposed that a PrPSc oligomer or
polymer recruits PrPc, which then converts to
PrPSc.
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the conversion of PrPC to PrPSc as a consequence
of a disease process in which PrPC might act as a
receptor for the infectious agent
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Scrapie. Naturally occurring scrapie in sheep and
goats has a duration of 2-6 months and typically
appears between the age of 2.5-4.5. Bovine
Spongiform Encephalopathy Clinical signs of
bovine spongiform encephalopathy (BSE) typically
appear at the age of 4-5 as progressive
apprehension, hyperaesthesia, and incoordination
of gait with a duration of 1-6 months. Human
TSEs Creutzfeldt-Jakob disease. The age of
onset of the disorder typically lies between
the age of 50 and 75. CJD occurs worldwide with
an incidence of approximately 0.5 cases per
million per annum. Iatrogenic cases are extremely
rare. Ca. 15 of all CJD cases represent
familial CJD with a dominant pattern of
inheritance. GSS (Gertsmann-Straussler
syndrome) in patients typically between 35-55
years of age as a slowly progressive ataxia of
2-10 years duration. GSS is nearly always
described in a familial context it occurs in
approximately 1 per 107 people. Kuru. It was
observed predominantly among children and adult
females and had a duration of 3-9 months. It is
confined to the Fore tribe of Papua New Guinea
(PNG), and is caused by cannibalistic rituals,
specifically the preparation and eating of human
brains Fatal familial insomnia (FFI) Most
patients were between the ages of 40 and 60
disease duration was 7-18 months. The occurrence
of fatal familial insomnia (FFI) is associated
with the same codon 178 aspartic acid to
asparagine mutation. Experimental TSE.
Neuropathology of experimental TSE is mostly
studied in hamsters and mice because of the
relatively short incubation times and the
convenience of animal keeping. Animals are
usually inoculated intracerebrally.