Prion Disease

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Prion Disease

• Mark F. Shinnick
• March 24, 2007

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QUESTIONSWhat key genetic difference
characterizes Prions apart from all earlier-known
forms of infection?Which of the two forms of
Prions is regarded as infectious, and what effect
does it play a role in producing in
non-infectious Prions ?Is there a chemical
difference between infectious, and non-infectious
prions? In what tissue type do prions become
concentrated? How is Prion infection most
typically acquired?Since no cure is known,
why is mere Prion infection still not a automatic
death sentence?Name one type of species which
is used to demonstrate Prion infection.Name a
wild animal population that is experiencing a
Prion infection epidemic.
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BULLET POINTSPrions - a new biological
principle of infection .by a mere protein
segment, not a whole genome!! All cases of
Prion disease are fatal.2 types of prions
exist Pathogenic and non Pathogenic, both
chemically the same. A physically twisted
infectious Prion protein is somehow capable of
effecting twisting of other prions and, after a
short or very lengthy delay since infection,
accumulations cause rapid and fatal disease
states in the brains and nervous clusters of man
and animals.The twisted or conformal-changed
prion affects non-twisted Prions.Until prions
were discovered, duplication of a infectious
particle without a genome was considered
impossible.We acquire infection by eating
infected meat/nervous tissue. Infection does not
automatically mean disease. A long possible
latency for humans. Infection within some wild
animal populations, like Elk and Deer, is rapidly
spreading.Transgenic species, such as mice,
have been created Prion-free. They can then be
purposely infected with pathogenic prions for
research.
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Presentation of the Nobel Prize in Physiology or
Medicine 1997This year's Nobel Prize in
Physiology or Medicine has been awarded to
Stanley B. Prusiner for his discovery of prions -
a new biological principle of infection. What
is a Prion? It is a small infectious protein
capable of causing fatal dementia-like diseases
in man and animals.Until prions were
discovered, duplication without a genome was
considered impossible. Stanley Prusiner,Your
discovery of the prions has established a novel
principle of infection and opened up a new and
exciting area in medical research. On behalf of
the Nobel Assembly at the Karolinska Institute I
wish to convey to you my warmest congratulations
and I now ask you to step forward to receive your
Nobel Prize from the hands of His Majesty the
King.(Prusiner used sheep in his prion
research.)
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Prions are small protein segments from membranes.
There turns out to be at least two forms of
Prion one misshapened PrPS, the other not PrP.
The S represents the Prion for Scrapie,the
sheep prion)Non-infectious Prions undergo a
reconformation , a misfoldingapparently
after being influenced in a unknown way by their
misshapened sisters. Chemically they appear the
same! Infectous Prions migrate up the nerves
and into the brain and heart. The accumulation of
these abnormal prions in the central nervous
system, the heart, or possibly other sites not
yet discovered is what brings on disease.
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• Prion Understanding Milestones
• 1966, Alper observed small target size of the
  infectious material to UV inactivation at 254 nm
  (Alper et al., 1966 Alper et al., 1967
• In 1967, Griffith had suggested reconformation
  of proteins.
• In 1993, Weissman showed PrP-deficient mice were
  immune to Prion infection. Established PrP
  protein as essential component of the disease.
  PrPC is a soluble protein, the PrPSc form is
  stubbornly insoluble Jonathan S. Weissman

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• Prion Understanding Milestones
• Similar Tissue levels of PrP mRNA were found in
  uninfected and Scrapie-infected tissues.
• So PrPSc Was not normally replicating.Prusiner,
  S.B. Science 216, 136-144 (1982).
• By 1985 the gene encoding the PrPSc Prion
  protein was found by various researchers to be
  expressed in all animals tested, humans too.
• Definition Exon The region of a gene that
  contains the code for producing protein. Each
  exon codes for a specific portion of the complete
  protein. Exons are separated by introns, long
  regions of DNA that have no apparent function.
• PrP derives from a host protein encoded by a
  single-copy gene having three known exons in
  mice, cattle and sheep but only two exons in
  hamsters and humans.
• IBR/CSI Center for Developmental Neuroscience and
  Developmental Disabilities, Staten Island, NY
  10314, USA.

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• The Scrapie agent is very small. Could not be
  affected by UV and is
• resistant to proteases
• This got Prusiners attention.
• By 1981 He had purified the agent 100- to
  1,000-fold with respect to protein.
• Prusiner, S.B. et al., Proc. Natl. Acad. Sci. 78,
  6675-6679 (1981)
• He termed the
• Normal Prion protein PrPC, Infectious form
  PrPSc

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The term Prion was coined by Stanley B. Prusiner
1982 for a "proteinaceous infectious particle
that lacks nucleic acid

• He purified apparent cause for mad cow disease,
• Bovine Spongiform Encephalopathy (BSE)
• -Infection route eating contaminated bovine
  meat/nerve tissue.
• Such infection has some other animal variants
• Scrapie sheep (18th century) (PrPS prion)
• TME (transmissible mink encephalopathy)
  mink
• CWD (chronic wasting disease) muledeer,
  elk
• (The incidence of chronic wasting disease with
  elk appears to be spreading rapidly.)
• THE UNDERSTANDING ABOUT PRION EFFECTS IN ANIMALS
  GROWS ITS A BRAND NEW FIELD.

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• Transmissible spongiform encephalopathies (TSEs)
• Reported Instances Distribution
• -Infection route eating contaminated bovine
  meat/nerve tissue.

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• Disinfection
• Prusiner found that
• sodium dodecyl sulfate, phenol, urea, digestion
  with proteinase K and trypsin, and chemical
  modification with diethyl pyrocarbonate,
  deactivated these PrPSc proteins.
• Prusiner, S.B. Science 216, 136-144 (1982).
• Ozone was found by other scientists to work under
  specific conditions.
• Commonly, prion-infected materials are
  incinerated.

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More recently, infectious prions found
concentrated in hearts of transgenic mice. False
color image of a mouse heart infected with
Scrapie.

• Prion-induced amyloid heart disease with high
  blood infectivity in transgenic mice, (Science,
  31394-97 (2006)
• Until now, Prion disease has been thought of as
  a chronic neurological condition, says Scripps
  Research Professor Michael B. Oldstone 2006

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• For Humans, diseases recently seen as Prion in
  origin are
• nv-CJD or v-CJD are caused by a strain very
  much like the BSE agent. Some people now call
  this disease Human BSE (2006) Work seeks to
  create immunity.
• CJD Creutzfeld-Jacob Disease (1920s)
  1 in 10,000 humans (likely more) infected with
  CJD at the time of death. Infection does not
  denote a disease state. Disease appears more
  prone after age 60. (http//www.tulane.edu/dmsand
  er/WWW/335/Prions.html)
• GSS Gerstmann-Straussler-Scheinker
  syndrome
• FFI Fatal familial Insomnia
• Kuru tremble" Fore highlands of New
  Guinea (1950s) (No new infections noted since
  1959)
• Alpers Syndrome
• AS WITH ANIMALS, THIS LIST IS EXPANDING WITH
  NEW HUMAN PRION RESEARCH. ITS A BRAND NEW
  FIELD.

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Summary-Prions are small protein segments from
membranes -In the presence of infectious prions,
non-infectious prions become reconformed and
infectious.-Normal Prions seem Ok. Its the
twisted ones that affect other Prions, aggregate,
and cause damage. Chemically, both Prions are
the same!!-Transgenic mice without any Prion
incidence are used to distinctly show Prion
infection.-Human Infection route eating
contaminated meat/nerve tissue.-Disease now
known to affect heart of mice.-Human incidence
of infection estimated 1-10,000, but this figure
is believed to be low.
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The Handout for this presentation available
athttp//firestormer.com/PrionDisease.htm
http//firestormer.com/PrionDisease.pptAdditiona
l ReferencesTeam Finds Crucial Protein Role In
Deadly Prion SpreadEvidence builds that virus
spurs mad cowBoffins reverse 'mad cow disease'
in micehttp//www.thisislondon.co.uk/news/article
-23383811-details/Boffins20reverse20'mad20cow2
0disease'20in20mice/article.dohttp//www.organ
icconsumers.org/madcow.cfmhttp//www.pbs.org/wgb
h/nova/madcow/http//www.whyfiles.org/012mad_cow
/http//www.fda.gov/oc/opacom/hottopics/bse.html