Proteins are fundamental components of
all living cells:
Actin and myosin,Keratin
“All are proteins”
The most common shapes are the alpha helix
and the beta conformation.
α helix β sheet
Secondary structure of a protein
Examples of alpha helices
and beta sheets
Only one of these many ways allows the protein
to function properly.
Too much of a misfolded protein could be worse
than too little of a normally folded one.
This is because a misfolded protein can actually
poison the cells around it.
Why do proteins fold ?
To cary out their function a protein should fold
and attain stability
Transmissibility in 1943 when a population of
Scottish sheep was inoculated against a
common virus with a formalin extract of
lymphoid tissue unknowingly derieved from
an animal with scrapie after two years nearly
10 of flock developed Scrapie.
History of Prions
Sometimes a scientific discovery shakes
the confidence of scientists, making them
question whether they truly understand
nature's "ground rules."
That's exactly what prions have done to
scientists, understanding of the ground
rules for infectious diseases.
Confusion created by Prions
After some years a clinically and pathologically
Similar human disease KURU meaning “trembling”.
Lead to hypotheses that the nature
of infectious agent ranging from a Replicating
polysaccharide to Nucleo protein complex
Filterable, formalin treatment didn’t completely
Kuru victims- lose the ability to walk, talk, and
The prototype (18th
century in England)
Causes intense itching to make the sheep
scrape off their wool
A natural progressive brain disease
Evidence of transmissibility during
Dr Stanely Prusiner
The Prion Hypothesis
“ a replicating protein”
The molecular nature was a mystery till 15 years
Stanley Prusiner showed its assosciation with a
Activity of prion was inactivated by
proteinase K, Diethylpyrocarbonate, Urea,
Phenol and SDS.
Activity not lost by nuclease treatments
or UV irrradiation.
Nature of prions
PrP is a 250 amino-acid residue glycosylated protein
connected to GPI-anchor.
The primary structure of PrP encoded by the gene of a
normal was found to be identical to that encoded by a
c DNA from a scrapie infected animal
Ab against prP 27-30 identified the prp protein
in the brain of uninfected animals and in many
tissues as a 33-35KDa glycosylated
The normal protein is called
Nomenclature of Prion Protein
has the ability to convert
A protein of identical size was also observed in scrapie-infected
Limited proteinase k digestion
Prpc completely degraded.
Prpsc a protein in infected
Brain was only partially
66 aa on –NH2 terminus
Yields PrP 27-30
Proteinaceous infectious particles
Abnormal proteins that have an affinity for the
Very highly resistant to heating (survive
Not sensitive to irradiation
Not destroyed by enzymes that damage DNA
Sensitive to protein denaturing agents
Characteristic features of Prions
Abnormal prions contact and change the
shapes of other normal prions in the nerve cell.
The nerve cell tries to get rid of them
When the cell dies, the abnormal prions are
released to infect other cells.
Large, sponge-like holes are left where many cells
Sheep - Scrapie Spongiform Encephalopathy.
Chronic Wasting Disease -Elk, Deer
Cow - Bovine spongiform encephalopaty
Human - Creutzfeldt-Jakobs Disease
Kind of Disease they cause in Different animals
Cerebral cortex : loss of memory and mental acuity,visual impairment (CJD)
Thalamus : Damage to the thalamus may result in insomnia (FFI)
Cerebellum : problems to coordinate body movements and difficulties to walk
Brain stem : In the mad cow disease (BSE), the brain stem is affected
Prion replication theories
2) Splitting theory
1) The nucleated polymerization theory
Jarret and Lansbury, (Cell 1993)
How are these abnormal proteins acquired?
A mutation in the prion gene in a brain
Inherit the abnormal gene from your
Ingestion of the protein
Humans could be accidentally infected
with the protein (iatrogenic) Needles,
Tissue, Pituitary extracts
How are Prion Diseses Usually Diagnosed ?
There is no blood test to detect the presence of
Currently there are two laboratory methods to
confirm a diagnosis:
– Microscopic examination of the brain tissue
– Special staining and microscopic techniques to
detect the partially-proteinase resistant form of
the prion (PrP) protein. SDS PAGE
Bovine Spongiform Encephalopathy
First noted in UK in early 1985
Animals fed rendered sheep meal
Prevalence peaked at about 35,000
2 to 4 year incubation time (longer?)
Loss of motor control, other neural
Following the onset of clinical signs, the
animals condition deteriorates until it either
dies or is destroyed.
This process usually takes from 2 weeks to 6
Most cases in Great Britain (where it was first
detected) have occurred in dairy cows
between 3 to 6 years of age.
How Does it Progress?
There are three phases of BSE in
The first phase:
Low infectivity rate, and the cow does not pose a large
threat to humans at this level
The second phase:
Symptoms are not evident, but the infectivity level is
The prion agent is abundant in both the spinal chord and
the brain – the cow is a risk to public health
The third phase:
Cattle affected by BSE
degeneration of the
Affected animals may display changes
in temperament, nervousness or
Prions in cattle are mainly from the carcasses
of scrapie-infected sheep
Infected sheep brains and other sheep
byproducts infected with scrapie is used to
feed cattle with the meat and bone meal
The prions are concentrated in the brain, and
spinal cord of these animals
How Prions transmitted from Sheep to Cattle?
UK still had about 200 BSE cases in 2005.
Portugal and Spain are still increasing in
numbers of BSE cases.
The shock wave ripples across the world.
Import bans imposed by many other nations have cut deeply into
the US beef industry
Direct and indirect economic activity from the industry adds up to
$188 billion annually, making it the largest portion of the nation's
food and fiber industry in US
Japan which had been the largest importer of US beef - continues
to demand that all US cattle scheduled for export be tested for
One challenge is that the animals have to be killed in order to test
Mad Cow Disease in
When cattle brains and other cattle byproducts
infected with BSE are ingested by humans, there
is a risk of developing the Creutzfeldt-Jakob Disease
How did BSE Transfer to Humans
Sheep with Scrapie used in Meat and Bone
Meal (MBM) – known as “Offal”
MBM fed to cattle
Infected Beef eaten by humans
Not affected by cooking
Creutzfeldt-Jakob disease (CJD)
Identified by Creutzfeldt and Jakob (1920)
A progressive fatal neurodegenerative disease of
Characterized by seizures, massive
Incidence about 1/1,000,000
CJD is classified into 2 forms:
Classic CJD & Variant CJD
Classic CJD can be transmitted to other species,
however other animals cannot carry it. Variant Creutzfeldtt-Jakob Disease (vCJD), is
caused by the consumption of BSE infected
First 10 cases of variant CJD were observed
in 1996, ten years after the outbreak of BSE in
Variant CJD seems to affect mostly young patients
New Treatment for vCJD?
A 19-year-old male from Belfast has been
treated with pentosan polysulphate by injection
into the brain
There is no Cure for
Mad Cow Disease
Prevention is the