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PRIONS Defn: small pr oteinaceous i nfectious particles that resist inactivation by procedures that modify viruses an - PowerPoint PPT Presentation

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PRIONS Defn: small pr oteinaceous i nfectious particles that resist inactivation by procedures that modify viruses and nucleic acids. Prion / Amyloid Diseases. Prion Diseases High levels of misfolded prion proteins Transmissible. Scrapie BSE Kuru Creutzfeldt-Jakob disease.

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PRIONSDefn: small proteinaceous infectious particles that resist inactivation by procedures that modify viruses and nucleic acids

Prion amyloid diseases l.jpg
Prion / Amyloid Diseases

  • Prion Diseases

  • High levels of misfolded prion proteins

  • Transmissible




Creutzfeldt-Jakob disease

  • Amyloid Diseases

  • Amyloid Fibers Found in Brain

  • Not Transmissible

Alzheimer’s (~ 4.5 million, US)

Parkinson’s (~ 500,000, US)

Huntington’s (~ 30,000 US)

Prion /Amyloid diseases are usually neurodegenerative.

Courtesy of Sid Taylor, MUW

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CJD is a neurological disease

Occurs sporadically in humans at a ratio of 1 per 1 million people

Estimated that 1 per 10,000 people have CJD at the time of death

(estimate could be inaccurate as CJD could be mistaken

for similar neurological diseases)

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Two types of CJD (genetic—hereditary and infectious)

  • CJD naturally occurring due to a mutation in a gene that encodes

  • the PrPc neural protein.

  • vCJD infectious caused by consuming beef from cattle with BSE

  • who are infected with the PrPsc protein

  • The neural proteins PrPc and PrPsc look different so one can tell the

  • difference between infectious and hereditary CJD

  • PrPsc is only transmissible from one human to another via

  • corneal transplants

  • brain surgery with contaminated instruments

  • contaminated brain probes

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Post-mortem examination of brain and neural tissue and

cells show

amyloid (starch-like) protein deposits—plaques between


Non-inflammatory lesions

Strange formations of neurons

Vacuoles—large membrane bound inclusion bodies

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CJD—clinical manifestations

Naturally occurring CJD affects humans at the age of


vCJD from transmissible prions can affect people

as early as 14

Disease manifestations


loss of motor control

Dementia—memory loss



death—a few months to 1.5 years after first symptoms

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Prion Properties

  • Prions are misfolded proteins.

    • Prion conformation is rich in b-sheets.

  • Prions aggregate in amyloids.

  • Prions are infectious.

    • Prion proteins induce conformational changes in other like proteins.

  • Prions can propagate into other cells.

Courtesy of Sid Taylor/MUW

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What are proteins

Proteins are made up of amino acids—each amino acid has its own

Chemical properties

The amino acids are linked together in by peptide bonds to form a

Primary Sequence like “beads on a string”--polypeptide

The primary sequence can form higher ordered structures called

Secondary Structures—these can be alpha helices or beta sheets

Region that has formed secondary structures can fold further to

bring these secondary structures together to form a tertiary structure.

Two or more identical or different tertiary structures come together to

form quaternary structures (more than one subunit)

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Within one chain alpha helices and beta sheets come together to form a 3o structure—this can be a functional protein

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Where do proteins end up? to form a 31. Stay in the cytoplasm2. Can be transported to the surface of the cell—membrane protein3. Can be secreted from the cell and into the external milieu--they may stay near the cells that secreted them --they may be circulated throughout the body

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Summary of previous notes to form a 3

  • CJD genetic anomaly vs. vCJD caused by consuming cows with

  • BSE.

  • PrPc (Prion protein cellular), alpha helical makeup, associated with

  • brain cell surface. Function unknown.

  • PrPsc (Prion protein that looks like protein that causes scrapies

  • in sheep), beta sheet structure, not associated with the cell surface.

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Summary of previous notes to form a 3

  • CJD genetic anomaly in humans

  • 1. PrPc is normally found on the surface of brain cells.

  • In some individuals a rare mutation on chromosome 20 can cause

  • PrPc to misfold into PrPsc .

  • 3. PrPsc dissociates from the cell membrane but causes PrPc that is

  • associated with the cell membrane to misfold and dissociate from the

  • cell surface.

  • 4. As PrPsc dissociates from the cell surface, more PrPc is translated in

  • brain cell and translocated to the surface/ PrPscinduces misfolding and

  • release of these proteins. Etcetera.

  • The accumulation of cell free PrPscforms proteinaceous plaques

  • between the brain cells

  • 6. Aggregated PrPsc is finally internalized into cells giving cells the

  • spongiform appearance.

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Summary of previous notes to form a 3

  • vCJD variant CJD from consuming infected beef from cows with BSE

  • BSE in cattle is analogous to CJD in humans in that it is a genetic

  • anomaly that leads to misfolding cell associated prion proteins into

  • pathological cell free proteins.

  • 2. In later stages of the disease process this is manifested as Mad

  • Cow Disease.

  • 3. The PrPsc from the cow can be transmitted to humans when humans

  • consume contaminated meat.

  • The misfolded protein enters the human’s nerve cells and travels

  • to the brain tissue.

  • 5. The pathological proteins from the cow causes the PrPc that is

  • naturally associated with the human cell membrane to misfold

  • and dissociate from the cell surface.

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Epidemiology to form a 3

PrPsc so far only transmissible to man from cows with BSE

Cattle can also transmit disease to domestic cats, sheep and pigs

Transmission from sheep and pigs to humans so far not documented

CWD –chronic wasting disease in elk and muledeer--a disease similar

to BSE in cattle not documented as transmissible to humans

PrPsc—not transmissible through milk or milk products

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Probable cause to form a 3

Hereditary BSE occurs naturally in cows at a low rate as CJD does

in humans.

1. Cows are butchered before they show manifestations of

disease such that PrPsc enters the human population at a low


2. Can be passed to the offspring and found associated with

placenta that contaminates grass that cows graze on

3. Farmers put ground up cattle in cattle feed, spreading BSE

in the bovine community—PrPsc enters the human population

at a high rate.

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PrPsc is spread from cows with BSE to humans to cause vCJD by consumption of such cows

PrPsc has been found concentrated in the following areas in cows


spinal cord

retina (eye)

distal ileum (small intestines)

neurons near the backbone

bone marrow

lymphatic tissue

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Transmission after beef consumption by consumption of such cows

PrPsc is taken up into Peyer’s patches—(mucousa associated lymphoid

Tissue (AKA MALT)—associated with the small intestines

T-cells induce its uptake by phagocytic calls that do not destroy

the protein

Cells leave MALT and enter the lymphatic tissue where they become

associated with

lymph nodes



Cells can leave the lymphatic system and enter the blood circulatory

system via the thoracic duct

Also lymphatic tissue is highly enervated so PrPsc can enter nerve cells

PrPsc moves up the axon of nerve cells to

spinal cord

eventually the brain

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Prevention and Cure by consumption of such cows


1. Don’t feed cows to cows

2. Destroy cow population once BSE found

3. Implement sensitive diagnostic tests to identify cows with

BSE before they show symptoms

There is no good way to destroy PrPsc in living material



Future treatments might include treatments currently used for

Alzheimer’s Disease.