Prion disease - Basic science (Dr Wille) Flashcards
What is the first prion disease that was described?
Scrapie
Is scrapie transmissible to humans?
No. Only contagious to sheep and goats; forms holes in their brains
What are the 3 manifestations of human prion disease?
- Sporaic: Creutzfeldt-Jakob disease (1920s)
- Inherited: Germlines mutation in PRNP gene (usually dominant)
- Infection: Transmitted via canibalism, medical procedures, consumption of infected fppd
What is most common of human prion disesae?
Sporadic (90%); familial (10%); infectious (1%)
What are the death chances w/ prion disease?
1:5000
What is kuru?
Prion disease trasmitted via ritualistic cannibalism in Fore tribe; discovered by Dr. Carleton Gajdusek;
Slow disease (5-50 years incubation); now extinct
What is bovine spongiform encephalopathy?
- Caused by feeding meat and bone meal to cattle (industrial cannibalism) –> mad cow’s disease
- No contamination to pastures like scrapie
- Three strains: classical; atypical and genetic
- Classical is transmitted to humans
What is the diff between sporadic CJD and variant CJD?
Sporadic affects elderly; variant affects younger
How many people showed signs of abnormal PrP deposits?
Apenndixes showed 1:2000 in Great Britain; high prevalence
Tonsils and appendix are where prions show up first
Where is chronic wasting disease found?
Deer, elk moos
Does CWD transmit via tissue, feces, saliva, urine?
YES. It is the most infectious prion disease we know
Slide 17
TRUE or false: are caribou threatened?
Yes, but it has not been trasnmitted yet
TRUE or False: Cooking reduces infectivity substantially
False, only marginally
Describe the overall human-human transmissions:
- Kuru: very efficient, not a problem anymore
- Iatrogenic CJD: very efficient, may be problem in UK
Describe the overall cattle-human transmissions:
BSE: Primary transmission relatively inefficient, incubation period uncertain; documented secondary transmirrion (eg blood transfusion)
Describe the overall sheep/goat-human transmissions:
Scrapie: no documented transmission, exposure suspected to be widespread.
Describe the overall deer/elk/moose-human transmissions:
CWD: Well documented exposure in increasing numbers, but no transmission so far; transmisison to non-human primates have been recorded
Is a prion a virus?
No
Where do prions first show up?
Specialized population of immune cells in illeum; peyers patch; these cells sample content of gut and present antigens to immune cells on other side (trains antigens to not be allergic to food); however they are also** responsible to transport prions **
immune cells can get infected and spread prions
How are prions taken up in the nervous sys?
Vagus nerve, mesenteric ganglion complex
What is a prion?
- Proteinacrous infectious particles
- Pathogens
- Composed of only protein
- Devoid of nucleic acid
- Coded by PRNP
- Can be folded into an infectious form PrpSc
Describe diff. between PrpC, PrpSc
PrpC: non infectious; cellular form of prion protein; PrpSc: infectious form, can be insoluble, resistant to proteolysis
What is Prp 27-30?
N-terminal truncation of PrpSc, still infectious
What is recPrp
recombinant, bacterially expressed prion protein, no post-translation moD.
not automatically infectious
What dogmas did the prion hypothesis break?
- All infectious agents have DNA or RNA (virology dogma)
- Info flows from DNA to rna to proteins only (mol. bio dogma)
- Native structure of a protein only determiend by amino acid seq (Anfinsen’s dogma)
What does GP1 do?
Anchors prion protein
What are ZIPs?
Prion protein ancestor; first exon went through retrotransposon event and became PrP gene; part of the SLC39 family - they have Irt-like proteins, Zn2+ transporters
Is Prnp found in lower vertebrates?
No
TRUE or FALSE: prion disease occurs in non mammals
False
Why is it hard to work w prion proteins?
aggregated; insoluble; infectious; hard to do x-ray crystallography and solution NMR
What do we know about prpsc strucutre?
Contain alot of beta sheet
current strucutre is the cryo EM strucutre
What is PIRIBS?
PARALLEL IN-REGISTER INTERMOLECULAR BETA-SHEET STRUCUTRE; shown to make up prion structures
Can also be four-rung beta solenoid strucutre
What is the prion cloud hypothesis?
Diff. conformations in diff. parts of the brain would contribute to diff. disease (major vs. minor conformations)
What is the refolding and seeding model for prion replication?
slide 48
What are the issues with immunization in prp?
- Immunization w misfolded Prpsc would lead to disease
- Immunization w native Prpc could be unspecific or cause autoimmune; however it would reduce substrate conc. and delay disease
- Immunization w unspecific protein results in unspecific/autoimmune response
What are the 3 most common genetic prion dieases?
P102L (GSS); D178N (FFI); E200K (fCJD)
