Transmissible Spongiform Encephalopathy

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Transmissible Spongiform Encephalopathy Prion
Protein Diseases Lisa Kennedy, Dylan Bradford,
Madi Hoagland Henefield, Anders Ohman Advisor
Dr. Todd Livdahl
Molecular Biology of the Pathogenesis of TSE
Background
Transmission Routes
Prion diseases (formally, Transmissible
Spongiform Encephalopathies) are
neurodegenerative conditions in mammals that are
hypothesized to be caused by an infectious
protein agent without the involvement of nucleic
information or additional transport vectors. The
theorized prion agent is a modified form of the
cell membrane protein PrPC, which is misfolded
into the pathogenic form of the protein, which is
referred to as PrPSc. These prion proteins are
able to convert normal protein molecules into the
prion form, and the proteins are extremely
resistant to denaturation by temperature or
chemical agents, making them both difficult to
destroy once in a host as well as capable of
surviving in an exposed environment for an
extended period of time. Prion diseases have
been documented for decades (centuries, in the
case of Scrapie), but the discovery of the prion
protein itself was made as recently as 1997 by
Stanley B. Prusiner, who won a Nobel Prize for
his work. The mechanics of the disease are still
largely unknown. They can affect many lineages of
mammals, from rodents to ruminants, as well as
humans. Prion disease in livestock has serious
implications for human food source populations,
as well as for potential infection in humans, as
the Bovine Spongiform Encephalopathy may
potentially be linked to a variant of
Creutzfeldt-Jakob Disease in humans. There is no
current cure, inoculation, or treatment for prion
diseases, and livestock protection strategies
largely include quarantine and destruction of
infected organisms. Symptoms TSEs cause the
formation of holes in the host nervous tissue,
causing a sponge-like appearance from which the
term spongiform is derived. Damage to the
nervous tissue causes a number of deteriorative
cognitive and behavioral conditions in prion
hosts of all susceptible species, typically
including dementia, acute mood changes, and
issues with physical coordination and control.
It is commonly held that prion diseases are
mainly transmitted between animals via ingestion
or orally. A number of ingestion routes have
been identified that cause disease in humans as
well as other animals including deer, elk, and
cattle. The most common and surest way is to
ingest tissue from an infected animal, the brain
tissue having the highest concentration of
dangerous prions. Omnivorous and carnivorous
animals are susceptible to this mode of
infection, and exhibits a very real danger to
human hunters of deer and elk. A study of humans
that were exposed to Chronic Wasting Disease (a
closely related prion disease) via hunted deer at
a wild game feast suggested two levels of risk,
exposure and ingestion (Garruto et al. 2008).
Those subject that had actually ingested venison
that could have come from an infected deer were
said to be of high-risk and are currently under
close watch in case CWD is found to transmit
between deer and humans. For herbivores it was
found that prions, in the form of Scrapie Agent
263k, are able to stay dormant in soil for at
least as long as 29 months and cause infection
(Seidel et al. 2007). The study was done using
Syrian hamsters and PrPSC were found to infect
and proliferate within the hamsters when fed soil
samples. Aqueous extract was also shown to
induce disease in the reporter animals. These
findings suggest a highly dangerous scenario for
cattle and sheep flocks. Prions can be deposited
by decaying animals, as well as infected organs
including placenta, amniotic fluid, and possibly
urine (Gregori et al. 2008), making grazing
animals highly susceptible. There still remains
much research to be done on prion diseases as a
whole including transmission routes. The way
they are passed between animals is very important
to determine if only to protect humans from
possible cross-species infection. Given the
amount of red meat consumed in the United States,
a large portion of infected but undetected meat
due to a lack of knowledge could cause a large
loss of life.
Prion disease are unique in that they are
transmissible particles that lack any form of
nucleic acid, and yet are still infectious
(Prusiner, 1998). While prion diseases are not
completely understood, it is clear the disease is
caused by an accumulation in the brain of a
misfolded cellular protein known as the prion
protein (PrPc) (Campana et al., 2008). The
normally occurring prion protein is converted
into the modified infectious protein PrPSc
posttranslationally. During this process PrPc
misfolds into PrPSc which contains a high number
of ß-sheets. The process during which the normal
protein changes to the abnormal takes place when
some of the a-helices and coils of its structure
refold into ß-sheets. This structural alteration
causes less understood but still profound changes
in the chemical properties of the PrP. The
changes that result in the PrPSc have been shown
to act as a template upon which PrPc is refolded
into PrPSc (Prusiner, 1998). This is how the
misfolded protein is able to become infectious to
other prion proteins around it. Furthermore,
PrPSc has shown the ability to resist degradation
even after the death of its host for up to months
or even years at a time, and still be infectious
to a new host if picked up.
Modeling the System
The model below calculates the number of new
cases of BSE that result from the use of infected
BSE cattle in cattle feed. The practice of
recycling cattle was relatively common before
the outbreaks of BSE in the UK. This STELLA
model (fig. 1) utilizes data used in a published
model used to calculate the hypothetical
reproductive ratio of BSE, as well as actual data
on the cattle population of the UK in 1986.
 
Types of TSE
Prion disease occurs in a number of different
mammals, and strains of prion disease typically
only affect peers in the species and
closely-related lineages (Prusiner, S.B. et al
1991). There are three primary categories of
prion diseases Sporadic, where the cause is
unknown Familial, where the disease is caused
by the genetics of the host and Acquired, which
is transmissible between organisms, either
directly or through the environment. There are
four primary prion diseases that affect humans
Creutzfeldt-Jakob Disease, Kuru, Fatal Familial
Insomnia, and Gerstmann-Straussler-Scheinker
Syndrome. CJD has variant strains in all three
categories, while Kuru is an Acquired disease and
both FFI and GSSS are Familial (Soldevila, M. et
al 2006). Symptoms of CJD, the most common human
prion disease with 1-2 instances in a million
people annually, has the symptoms of dementia,
issues with coordination, and visual
hallucinations. GSSS shares the symptoms of
dementia and coordination problems, but also
results in difficulty speaking. Sufferers of Kuru
have laughing fits and trembling fits. FFI causes
insomnia, hallucinations, and also dementia
(Monari, L. et al 1994). Deer, Elks, and Moose
are affected by Chronic Wasting Disease, an
Acquired condition that is transmissible directly
or through contact with a shared environment
(Joly, D.O. et al 2003). CWD was first contained
to the Central United States, but has since
spread to multiple areas of the US and Canada,
including game parks. It causes changes in host
mood, diet, and behavior. Sheep and Goats are
affected by Scrapie, the oldest-known prion
disease first named in 1732 (www.defra.gov.uk).
Scrapie affects both the nervous system as well
as the tonsils and the distal ileum, and causes
behavioral abnormalities such as the compulsive
scraping of the host on objects in the
environment from which the diseases name is
derived. Although found in Europe and in America,
successful quarantine has kept the disease out of
Oceanian populations (Parsonson, I.M.
1996). Cows are affected by Bovine Spongiform
Encephalopathy. While BSE (a.k.a. Mad Cow
Disease) is a strictly Familial disease, domestic
animal practices for feeding livestock resulted
in direct consumption of infected brain tissue as
animal feed, and therefore spread the disease
from individual to individual (Prusiner, S.B.
1997). BSE leads to the formation of protein
fibers in the brain, leading to the presence of
holes in the tissue. Symptoms include nervous or
aggressive behavior, weight loss, and
coordination problems, but can take years to
actually appear.
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1947 Transmissible mink encephalopathy
1967 Chronic Wasting Disease CWD captivity
1921 Creutzfeldt-Jakob disease (CJD)
1996 Variant Creutzfeldt-Jakob Disease
1981 CWD wild populations
TIMELINE
Kuru 1959
1732 Scrapie
1936 Gerstmann Straussler-Scheinker Syndrome
(GSSS)
2003 Feline spongiform encephalopathy
1974 Fatal Familial Insomnia
1986 BSE
1997 Prion protein discovered
Timeline not to scale The dates indicate
descriptions and identifications of the
respective diseases. At the earlier dates, cause
of disease by the prion protein was not
known By Stanley B. Prusiner winner of the
Nobel Prize in Physiology or Medicine 1997