Class 9A: Prions Flashcards
What is a prion?
A proteinaceous infectious agent
-can transmit disease & replicate itself without the need
for a nucleic acid genome!
What makes a prion unique?
-can transmit disease & replicate itself without the need
for a nucleic acid genome!
-only a single species of protein
= prion protein (PrP)
= A new type of infectious agent
The discovery of prions
What animals?
sheep
cattle
The discovery of prions: sheep
Sheep developed a disease known as _______ in some flocks
–Sheep develop a disease known as “scrapie” in some flocks
- animals itch, rub and scrape their skin
- develop tremors and behavioural changes
- usually fatal
What does examination of a scrapie brain show?
- Examination of scrapie brain shows:
- “holes” in the cortex & cerebellum –> spongiform encephalopathy
- -> no conventional infectious agent
And yet…..
-animals who were infected could transmit this disease to healthy animals in the same or other flocks, if allowed contact with them
The discovery of prions: cattle
–Cattle have been fed meat & bone meal (sheep) since the 1920s in
Britain –> became more extensive in 1970s
-1980s – bovine spongiform encephalopathy (BSE) seen in cattle
= mad cow disease
Scrapie in sheep is a disease that is very similar to _______ in cattle.
mad cow disease
- disease very similar to scrapie
- infectious agent jumped a species barrier from sheep to cattle
- cattle were fed infectious material
- millions of cows slaughtered
- risk of transmission to humans
Did bovine spongiform encephalopathy (BSE) cross the species barrier?
YES
However, BSE did jump the species barrier and causes a disease in humans
= new variant Creutzfeld-Jacob disease (nvCJD)
- acquired through consumption of infected meat
- 10-15 new cases each year in the UK since 1994
The discovery of prions: humans
–1950s – a transmissible spongiform encephalopathy discovered in
humans
-the Fore tribe in Papua new Guinea
-tremors, dementia and death within 1 year of onset of symptoms
-was wiping out the tribe = very high incidence
=Kuru (trembling disease)
- Traced to a ritual cannibalism of brains of the deceased
- infectious agent in brains transmitted to healthy members
The discovery of prions: humans
How was the transmissibility of this disease proven?
-Dr. Carleton Gajdusek proved the transmissibility of this disease
-injected brain tissue from the funeral ritual into chimps
= disease seen in animals
- awarded the Nobel in 1976
- convinced it was an unknown virus!
-transmissibility discovered after corneal transplants, intracerebral electrode use
(contaminated) and human growth hormone preparations from cadavers were used on
healthy humans
What does TSE stand for?
transmissible spongiform encephalopathies (TSEs)
The infectious agent in prion diseases
Name some of the key observations that were made (3) about the trasnfer of the infectious agent (from scrapie, BSE, to human TSE brain to chimps)
Transfer of the infectious agent from scrapie, BSE or human TSE brain
to chimps was a key part of this identification process
-disease often took months to appear –> long incubation times
Several key observations were made:
- Agents that damage nucleic acids had minimal effect on the
transmissibility of prions (ionizing radiation)
2. Compounds that affected the integrity of proteins, however, did impact transmission (SDS, strong alkali etc.)
- Infectious material was enriched in a 27-30Kd protein
What is the infectious agent in prion diseases?
27-30Kd protein, PrP
In humans, PrP is encoded by the ______ gene in humans
PrP is encoded by the PRNP gene in humans
- expressed in almost all cell types
- including neurons, dendritic cells and lymphocytes
-encodes a 207-amino acid protein called PrPc
for cellular isoform
What is PrPc?
Highly conserved among mammals
SYNTHESIS
-Synthesis begins in the ER = has N-terminal signal peptide
- Has 2 glycosylation sites to which oligosaccharide chains are added
- 24 AAs in the C-terminus are then cleaved = signal for GPI anchoring
- A C-terminal GPI anchor is added to anchor the protein to the ER membrane
- Moves to Golgi = complex glycans added
- Secretory vesicle transport to the PM and anchored there by GPI lipid anchor
