Exam IV: Lecture 16 Flashcards
What are Koch’s modified postulates?
- Pathogen must be present in every case of the disease
- Pathogen must be isolated from the host with the disease and grown in cells in culture
- Disease must be reproduced when a pure culture of the pathogen is inoculated or tissue into a healthy susceptible host
- Pathogen must be recoverable from the experimentally infected host
What does TSE stand for?
Transmissible spongiform encephalopathies
What is TSE?
Progressive, fatal disease of humans and other animals
Characterized by neuronal loss > spongiform degeneration in brain tissue
Can also be accompanied by amyloid plaques or fibrils
What are some examples of diseases that are TSEs? (4)
- Kuru
- CJD (Creutzfeldt-Jakob Disease)
- Gerstmann-Straussler-Scheinker Syndrom
- Fatal Familial Insomnia
What is the fatality rate of TSE diseases?
100%
Death occurs withing 6mo-1 year
How does one contract TSE?
- Acquired (Ingestion of infected tissue or iatogenic)
- Sporadic mutation
- Inherited
A mutation in what gene can cause someone to be predisposed to sporadic TSEs? What chromosome is it located on?
PRNP gene
Chromosome 20
What 3 human TSEs are inherited?
- CJD
- GSS
- FFI
What is scrapie? When was it first described? How was it transmitted? What is its namesake? Does it spread to humans?
Scrapie was first described in 18th C
Sheep contracted the disease by eating the grass contaminated by afterbirth
Sheep would become “itchy” and scrape off their wool
it is not known to spread to humans
What does scrapie cause in the sheep?
Degeneration of brain tissue
There is a similar disease to scrapie in deer and elk. What is it called?
Chronic wasting disease
What is Kuru? Where was it found? How was it transmitted? What is its namesake?
Disease found in New Guinea
Fore people eat part of dead bodies of relatives
Kuru = to be afraid/to shiver
Why were the women and children affected differently by Kuru than the men? What did that signify?
Only the women and children would get Kuru because they were the only ones that ate the brain of the relatives
Told researchers that the disease existed in the brain
What was the pathology of Kuru?
Blurred speech, dementia, inability to walk, speak, see
Eventual death
Is Kuru an old disease? Is Kuru still a problem today?
Kuru is not an old disease, someone from the tribe acquired a mutation (1900) > Kuru
It is not still a problem today because researchers convinced the Fore people to stop cannibalism and Kuru went away (1950)
What are the 3 stages of Kuru?
- Ambulatn stage
- Sedentary stage
- Terminal stage
What is the life span of someone with Kuru?
Adults: 12-18 months
Children: 3-12 months
Transmission of Kuru to primates in the lab from brain extracts was the first demonstration of TSE diseases
True
What is BSE? How was it transmitted?
Mad Cow Disease
Took cows that died from BSE > made meal out of the unwanted parts > feed it to the other cows > cows developed BSE
They thought that since the process of creating meal was so harsh meal wouldn’t have any bacteria or viruses. What does this tell us about prions?
They are very strong
What was BSE caused by?
nvCJD (new variant CJD)
Given the long incubation time of diseases such as Kuru ( up to 40 years), what is the concern?
That a large number of nvCJD cases could potentially arise over time
Is CJD a common or rare disease?
It is a rare disease that occurs sporadically
What are te 3 routs of acquiring CJD?
- Inherited mutation of the prion gene in dominant fashion
- Iatrogenic transmission during transplants of dura mater, corneal transplants, cadaveric pituitary-derived HGH
- Familial autosomal dominant CJD (5%)
Sporadic CJD (sCJD) occurs at what point in a person’s life? How is this different from new variant CJD (nvCJD)?
sCJD occurs in your 60s. Death in 5 months.
nvCJD occurs in teens-30s. Death in 1 year.
sCJD is characterized by what? What about nvCJD?
sCJD; dementia
nvCJD; psychiatric symptoms, usually depression
Identifying the prion protein was difficult. Tell me why.
proteases, DNAases, RNAases, high temps were not enough to sterilize the sample (i.e. it was nothing we knew how to stop - it did not contain DNA or RNA)
What does PRION stand for?
protienecious infectioun agent
Ultimately, how did we figure out it was the prion protein?
Mutations in the prion protein were found in hereditary cases of TSEs
What is the normal cellular protein called? What is the abnormal protein called?
PrP^c “cellular prion protein”
PrP^sc “scrapie prion protein”
What does the cellular prion protein do? What chromosome is it in? Does it exist in polymorphisms?
Attached to the membrane by glycoproteins
Binds to copper
Yes, it exists in polymorphisms
The prion protein is resistant to what 7 treatments?
- Proteases
- Organic solvents
- Alkaline reagents such as cleaners
- UV light
- Ethanol
- Formaldehyde
- High temperatures (>121C)
How long is the prion protein?
254 amino acids
2.5kb long mRNA
What specific mutations in PrP cause you to be prone to TSEs?
- Having a Met @ 129
2. Having Val @ 129
What is the life cycle of PrP?
Synthesized on rough ER > moves to plasma membrane > binds Cu2+ > cycled into endocytic vesicles > degraded or moved back to cell surface
folding to mutated version > mutated version is resistant to proteases > PrP^sc aggregate
Every person has different levels of PrP^c. If a person has lots of PrP^c what does this mean for the patient?
A person with high levels of PrP^c will progress through the disease more rapidly and with higher sensitivity
What is the molecular difference between PrP^c and PrP^sc?
PrP^c = alpha helices PrP^sc = beta sheets = more stable
How do normal PrP get converted to PrP^sc? Does the process require intact cells?
Normal can be converted to abnormal via exposure to an abnormal prion. Basically, the abnormal protein acts as enzyme
No, this process does not require intact cells
If prions cause neurodegeneration, how do they get into cow meat and then into our neurons?
While cows are being slaughtered > cut into spinal chord/nerve > prions get on muscle > we eat the muscle > prion come in contact with pryer’s patches in the stomach > retrograde transport to the brain
The PrP^sc forms an aggregate that is insoluble. What is the implication of this?
The conversion is irreversible
What is the immune response agaisnt prions?
There is none, there is no inflammation or antibodies
How do you prevent TSEs?
- No cannabalism
- Don’t feed healthy livestock infected meat
- Genetic monitoring
Inactivation of the mutated prions requires heating up to ____F?
800
Chemicals that interfere with which process might inhibit PrP^sc maturation include: (4)
- Endocytosis
- Exocytosis
- Transcellulr trafficking
- Protein degredation
PrP is only produced in neuronal tissue
True
