Prion disease - Basic science (Dr Wille)

Question 1

What is the first prion disease that was described?

Answer 1

Scrapie

Question 2

Is scrapie transmissible to humans?

Answer 2

No. Only contagious to sheep and goats; forms holes in their brains

Question 3

What are the 3 manifestations of human prion disease?

Answer 3

• Sporaic: Creutzfeldt-Jakob disease (1920s)
• Inherited: Germlines mutation in PRNP gene (usually dominant)
• Infection: Transmitted via canibalism, medical procedures, consumption of infected fppd

Question 4

What is most common of human prion disesae?

Answer 4

Sporadic (90%); familial (10%); infectious (1%)

Question 5

What are the death chances w/ prion disease?

Answer 5

1:5000

Question 6

What is kuru?

Answer 6

Prion disease trasmitted via ritualistic cannibalism in Fore tribe; discovered by Dr. Carleton Gajdusek;

Slow disease (5-50 years incubation); now extinct

Question 7

What is bovine spongiform encephalopathy?

Answer 7

• 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

Question 8

What is the diff between sporadic CJD and variant CJD?

Answer 8

Sporadic affects elderly; variant affects younger

Question 9

How many people showed signs of abnormal PrP deposits?

Answer 9

Apenndixes showed 1:2000 in Great Britain; high prevalence

Tonsils and appendix are where prions show up first

Question 10

Where is chronic wasting disease found?

Answer 10

Deer, elk moos

Question 11

Does CWD transmit via tissue, feces, saliva, urine?

Answer 11

YES. It is the most infectious prion disease we know

Slide 17

Question 12

TRUE or false: are caribou threatened?

Answer 12

Yes, but it has not been trasnmitted yet

Question 13

TRUE or False: Cooking reduces infectivity substantially

Answer 13

False, only marginally

Question 14

Describe the overall human-human transmissions:

Answer 14

• Kuru: very efficient, not a problem anymore
• Iatrogenic CJD: very efficient, may be problem in UK

Question 15

Describe the overall cattle-human transmissions:

Answer 15

BSE: Primary transmission relatively inefficient, incubation period uncertain; documented secondary transmirrion (eg blood transfusion)

Question 16

Describe the overall sheep/goat-human transmissions:

Answer 16

Scrapie: no documented transmission, exposure suspected to be widespread.

Question 17

Describe the overall deer/elk/moose-human transmissions:

Answer 17

CWD: Well documented exposure in increasing numbers, but no transmission so far; transmisison to non-human primates have been recorded

Question 18

Is a prion a virus?

Answer 18

No

Question 19

Where do prions first show up?

Answer 19

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

Question 20

How are prions taken up in the nervous sys?

Answer 20

Vagus nerve, mesenteric ganglion complex

Question 21

What is a prion?

Answer 21

• Proteinacrous infectious particles
• Pathogens
• Composed of only protein
• Devoid of nucleic acid
• Coded by PRNP
• Can be folded into an infectious form PrpSc

Question 22

Describe diff. between PrpC, PrpSc

Answer 22

PrpC: non infectious; cellular form of prion protein; PrpSc: infectious form, can be insoluble, resistant to proteolysis

Question 23

What is Prp 27-30?

Answer 23

N-terminal truncation of PrpSc, still infectious

Question 24

What is recPrp

Answer 24

recombinant, bacterially expressed prion protein, no post-translation moD.

not automatically infectious

Question 25

What dogmas did the prion hypothesis break?

Answer 25

1. All infectious agents have DNA or RNA (virology dogma) 2. Info flows from DNA to rna to proteins only (mol. bio dogma) 3. Native structure of a protein only determiend by amino acid seq (Anfinsen's dogma)

Question 26

What does GP1 do?

Answer 26

Anchors prion protein

Question 27

What are ZIPs?

Answer 27

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

Question 28

Is Prnp found in lower vertebrates?

Answer 28

No

Question 29

TRUE or FALSE: prion disease occurs in non mammals

Answer 29

False

Question 30

Why is it hard to work w prion proteins?

Answer 30

aggregated; insoluble; infectious; hard to do x-ray crystallography and solution NMR

Question 31

What do we know about prpsc strucutre?

Answer 31

Contain alot of beta sheet ## Footnote current strucutre is the cryo EM strucutre

Question 32

What is PIRIBS?

Answer 32

PARALLEL IN-REGISTER INTERMOLECULAR BETA-SHEET STRUCUTRE; shown to make up prion structures ## Footnote Can also be four-rung beta solenoid strucutre

Question 33

What is the prion cloud hypothesis?

Answer 33

Diff. conformations in diff. parts of the brain would contribute to diff. disease (major vs. minor conformations)

Question 34

What is the refolding and seeding model for prion replication?

Answer 34

slide 48

Question 35

What are the issues with immunization in prp?

Answer 35

1. Immunization w misfolded Prpsc would lead to disease 2. Immunization w native Prpc could be unspecific or cause autoimmune; however it would **reduce substrate conc. and delay disease** 3. Immunization w unspecific protein results in unspecific/autoimmune response

Question 36

What are the 3 most common genetic prion dieases?

Answer 36

P102L (GSS); D178N (FFI); E200K (fCJD)