Prions

Question 1

What are Transmissible spongiform encephalopathies (TSEs)?

Answer 1

neurodegenerative diseases, always fatal, no available therapies

Question 2

how are TSE’s transmissible?

Answer 2

experimentally through inoculation

Question 3

why “spongiform”?

Answer 3

microscopic vacuoles (lesions) in brain tissue are a feature that help identify the disease

Question 4

what is the infectious agent of TSEs?

Answer 4

prions (type of protein)

Question 5

What is Scrapie?

Answer 5

• oldest known TSE
• neurodegenerative disease in sheep and goals
• mother to offspring transmission
• not transmissible to humans

Question 6

What are the types of TSEs? What are the target hosts>

Answer 6

1. Scrapie (sheep and goats)
2. Bovive spongiform encephalopathy (BSE): mad cow disease
3. Creutzfeldt-Jakob Disease (CJD): human
4. Kuru: human
5. Chronic wasting disease (CWD): large herbivores

Question 7

TSEswereinitiallythoughttobe caused by

Answer 7

an unidentified “slow” virus (thought that transmissible infections require nucleic acid)

Question 8

How was it discovered that TSEs were caused by proteins?

Answer 8

• sensitivity to proteases indicates that the scrapie agent contained protein for infectivity
• resistant to inactivation by modification of nucleic acid

Question 9

Where are prions found?

Answer 9

surface of neurons

Question 10

What is the “natural” protein that turns to prions?

Answer 10

PrPc (cellular prion protein)
- highly conserved
- function unknown, potentially synaptic function
- not infectious

Question 11

What is the “infectious form” of prions?

Answer 11

PrPSc
- smallest known infectious agent
- (Scrapie Prion Protein)
- no nucleic acid

Question 12

why is no immune response evoked for prion PrPSc?

Answer 12

host protein

Question 13

How is PrPc different from PrPSc?

Answer 13

PrPSc has a structural difference - irreversible shape/conformation change:
- PrPc: alpha helices, PrPSc: beta sheets
- PrPc: soluble, PrPSc: insoluble
- PrPc: PK sensitive, PrPSc: PK resistant
- PrPc: no aggregation, PrPSc: aggregation

Question 14

what is proteinase k?

Answer 14

protein degrading enzyme to which PrPsc is immune mainly bc insoluble

Question 15

how does PrPSc spread?

Answer 15

not self-replication (like a bacteria)

PrPc converted to PrPSc

Question 16

PrPSc is resistant to

Answer 16

procedures that usually inactivate other infectious agents: heat (autoclaving), disinfectants, UV

Question 17

what are the steps for PrPc to PrPSc conversion?

Answer 17

1. PrPc produced by cell and secreted to cell surface
2. PrPSc aquired or produced by altered PrPc gene
3. PrPc reacts with PrPSc making a heterodimer on cell surface
4. PrPc converted to PrPSc
5. PrPSc positive feedback loop to convert more PrPc
6. PrPSc dimers (2) can also make oligomer with other PrPSc proteins
7. PrPSc is taken in by endocytosis but PrPSc accumulates in endosomes since insoluble = not degraded
8. PrPSc continuoes to accumulate as endosome contents are transferred to lysosomes
9. toxic -> cell death

Question 18

what occurred in the experiment when healthy mice are injected with brain fluid from Scrapie sheep?

Answer 18

• mice dont get sick bc proteins can’t replicate on their own

Question 19

the highest concentration of PrPC is in the

Answer 19

brain

Question 20

accumulation of prions in the brain causes

Answer 20

neuron death (gives spong-like look) = formation of amyloid plaques

Question 21

what are amyloids?

Answer 21

insoluble fibrous protein aggregates

Question 22

symptoms of TSEs?

Answer 22

1. long clinical period 5+ year exposure
2. personality
3. change
4. psychiatric issue (depression)
5. lack of coordination
6. involuntary jerking movements, unusual sensations, insomnia, confusion, or memory problems
7. severe mental, mobility, language impairment
8. death

Question 23

What gene is PrP encoded by?

Answer 23

prnp gene (host gene)

Question 24

what are the 3 characteristics of prion disease?

Answer 24

1. infectious
2. heritable (mutated prnp)
3. sporadic (normal prnp becomes mutated)

Question 25

Modes of transmission from most to least efficient for prions?

Answer 25

1. intracerebral 2. intravenous 3. intraperitoneal 4. subcutaneous (under skin) 5. intragastric (oral) | 1st 3 are experimental settings

Question 26

What caused Bovine spongiform encephalopathy?

Answer 26

feeding cow remains to live cows - cow developed sporadic mutation = PrPSc protein fed back into cow - transmitted to humans by consumption of cow brain or spinal cord

Question 27

What is the variant Creutzfeldt-Jakob Disease (vCJD)?

Answer 27

- a rare and fatal form of a TSE that affects humans - linked to the consumption of meat products derived from BSE-infected cattle

Question 28

What are the 3 types of Creutzfeldt-Jakob Disease (CJD)?

Answer 28

1. Sporadic CJD (~85%) 2. Hereditary (familial) CJD(~5-15%) 3. Iatrogenic CJD (<1%)

Question 29

What is Sporadic CJD

Answer 29

no known environmental source - **mutation generated**

Question 30

what is Hereditary (familial) CJD?

Answer 30

genetic mutation is associated with CJD – confirmed by genetic tests and family history - **protein misfolded**

Question 31

What is Iatrogenic CJD?

Answer 31

from a medical procedure such as surgery - **source has often been cadaveric dura matter grafts and contaminated neurosurgical equipment**

Question 32

Why do females have higher levels of kuru?

Answer 32

eat brain of person with sporadic mutation of PrPSc

Question 33

How was resistance acquired to CJD? How was this found out?

Answer 33

PrPc with M129V mutation is resistant to CJD - found in people exposed to Kuru that surved the epidemic - took 50 yrs to develop Kuru in these people

Question 34

What is Chronic wasting disease (CWD)? How is it transmitted)

Answer 34

- TSE of mule deer,white tail deer, elk, and moose - mode of transmission unknown - transmission to humans is unknown

Question 35

What was the case of acquiring vCJD in lab?

Answer 35

- 24 yr old prion lab tech handling brain sections from transgenic mice with human prion gene - skin puncture with forceps - patient diagnosed 7.5 years after and died 9 years after with vCJD - diagnosed through prion protein detection in cerebrospinal fluid

Question 36

what is Alzheimer's disease? cause?

Answer 36

fatal, progressive and degenerative disease that destroys brain cells CAUSE: B-amyloid oligomers build up in brain using PrPc receptor for amyloid beta

Question 37

what is a similarity between Prions and Alzheimers?

Answer 37

both diseases are dementing disorders that involve the deposition of protein aggregates