Transmissible Spongiform Encephalopathy

Prion Protein Diseases

Lisa Kennedy, Dylan Bradford, Madi Hoagland Henefield, Anders Ohman
Advisor: Dr. Todd Livdahl

Background Molecular Biology of the

Transmission Routes
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 diseases (formally, Transmissible Spongiform Encephalopathies) are neurodegenerative conditions in mammals that are Pathogenesis of TSE
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 PrP C, which is misfolded into the pathogenic form of the protein,
Prion disease are unique in that they are
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 transmissible particles that lack any form of nucleic acid,
capable of surviving in an exposed environment for an extended period of time. and yet are still infectious (Prusiner, 1998). While prion
Prion diseases have been documented for decades (centuries, in the case of Scrapie), but the discovery of the prion protein itself was diseases are not completely understood, it is clear the
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 disease is caused by an accumulation in the brain of a
unknown. They can affect many lineages of mammals, from rodents to ruminants, as well as humans. Prion disease in livestock has serious misfolded cellular protein known as the prion protein
implications for human food source populations, as well as for potential infection in humans, as the Bovine Spongiform Encephalopathy
(PrPc) (Campana et al., 2008).
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. The normally occurring prion protein is converted
into the modified infectious protein PrPSc
Symptoms: posttranslationally. During this process PrPc misfolds
TSEs cause the formation of holes in the host nervous tissue, causing a sponge-like appearance from which the term ‘spongiform’ is into PrPSc which contains a high number of β-sheets. The
derived. Damage to the nervous tissue causes a number of deteriorative cognitive and behavioral conditions in prion hosts of all susceptible process during which the normal protein changes to the
species, typically including dementia, acute mood changes, and issues with physical coordination and control.
abnormal takes place when some of the α-helices and
coils of its structure refold into β-sheets. This structural
alteration causes less understood but still profound
Modeling the System changes in the chemical properties of the PrP. The
changes that result in the PrPSc have been shown to act
The model below calculates the number of new cases of as a template upon which PrPc is refolded into PrPSc
Transmission Rate
BSE that result from the use of infected BSE cattle in cattle
Cattle population (Prusiner, 1998). This is how the misfolded protein is
feed. The practice of “recycling” cattle was relatively able to become infectious to other prion proteins around
BSE Infecctions BSE Cattle
common before the outbreaks of BSE in the UK. This it. Furthermore, PrPSc has shown the ability to resist
STELLA model (fig. 1) utilizes data used in a published degradation even after the death of its host for up to
model used to calculate the hypothetical reproductive ratio months or even years at a time, and still be infectious to a
of BSE, as well as actual data on the cattle population of
Proportion Infectivity new host if picked up.
the UK in 1986.

Types of TSE Infectivity Passed

Material with BSE Infectivity

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
Cattle p o p ulation 12. 7 million*
Reduction Rate
genetics of the host; and Acquired, which is transmissible between organisms, either of Infectvivity Trans mission rate .001
directly or through the environment.
Pr op or tio n infe ctivity .8 5
New Cases of BSE from MBM

There are four primary prion diseases that affect humans: Creutzfeldt-Jakob Disease,
Kuru, Fatal Familial Insomnia, and Gerstmann-Straussler-Scheinker Syndrome. CJD BSE infectivity in MBM
Red uctio n rate of infectivity .1
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 Cattle Feed with Pr op or tio n of MBM in Cattl e .2
common human prion disease with 1-2 instances in a million people annually, has the
Infected MBM
Redction of BSE Material Fe e d
symptoms of dementia, issues with coordination, and visual hallucinations. GSSS
Proportion of MBM
New cas e s o f BSE 34
3722
shares the symptoms of dementia and coordination problems, but also results in in Cattle Feed

difficulty speaking. Sufferers of Kuru have laughing fits and trembling fits. FFI
Graph 1
*so urc e : BSEinq uiry.g o v.uk
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. 1947: 1967: Chronic
1921: Transmissible Wasting 1981: CWD 1996: Variant
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
Creutzfeldt-Jakob mink Disease CWD: wild Creutzfeldt-
tonsils and the distal ileum, and causes behavioral abnormalities such as the disease (CJD) encephalopathy captivity populations Jakob Disease
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). TIMELINE
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 Kuru:
livestock resulted in direct consumption of infected brain tissue as animal feed, and 1732*: 1936: Gerstmann 1974: Fatal 1986: 1997: Prion 2003: Feline
therefore spread the disease from individual to individual (Prusiner, S.B. 1997). BSE Scrapie Straussler-Scheinker 1959 Familial BSE protein spongiform
leads to the formation of protein fibers in the brain, leading to the presence of holes in Syndrome (GSSS) Insomnia discovered*** encephalopathy
the tissue. Symptoms include nervous or aggressive behavior, weight loss, and
coordination problems, but can take years to actually appear. *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