Prions

Question 1

What was significant about surgical instruments used on CJ-diseased patients?

Answer 1

Four cases of iatrogenic transmission have occurred in patients undergoing neurosurgical procedures with instruments used in previous brain operations of CJ-diseased patients.

In blue: These transmissions occurred despite conventional sterilization of the instrumentation used on the source patients, which led to the subsequent iatrogenic transmissions!

Question 2

What is the only certain method of avoiding iatrogenic transmission of CJ-contaminated surgical instruments?

Answer 2

Incineration and discarding of instrument sets

Question 3

What is PRNP?

Answer 3

Prion protein: a naturally occurring CNS protein encoded by the PRNP gene

Question 4

What is PrPC?

Answer 4

Cellular prion protein

Question 5

What is the structure of PrPC?

Answer 5

Alpha-helical
Structured region at C-terminus
Unstructured region at amino-terminus

Question 6

What is the “Protein-only” hypothesis and who formulated it?

Answer 6

Stanley Prusiner posited that the prion protein alone, with NO nucleic acids, is responsible for transmissible forms of spongiform encephalopathy.

Question 7

What is PrPSc?

Answer 7

When a prion protein misfolds, it becomes PrPSc (for “Scrapie”). It accumulates in amyloid plaques in the brain, and causes neurodegeneration (mechanisms unknown).

Question 8

What are PrPSc fibrils?

Answer 8

When PrPC proteins (alpha-helix) misfold, they form trimers of PrPSc proteins (Beta sheets). When these trimer units stack up, they form fibrils.

Question 9

What is PrPres?

Answer 9

Largely synonymous for PrPSc. Abnormal, partially protease resistant Prion disease associated isoform of PrP.

Question 10

What is the autocatalytic model of PrP polymerization?

Answer 10

The conformational conversion of PrPC to PrPres is rare unless catalyzed by contact with an existing PrPres multimer.

Question 11

What is the noncatalytic model of PrP polymerization?

Answer 11

The conformational interchange between PrPC and PrPres is rapid, but the PrPres conformer is poorly populated unless stabilized by binding to an existing PrPres multimer.

Question 12

What molecules are involved in prion replication and prion infectivity?

Answer 12

Cofactors

Question 13

What does PrPC do normally?

Answer 13

It seems to act in signal transduction primarily in neurites

Question 14

What is the neurotoxic prion protein fragment?

Answer 14

Amino acids 106-126

Question 15

What is an ERAD?

Answer 15

Endoplasmic reticulum associated protein

Question 16

What are amyloidogenic proteins?

Answer 16

Proteins that contain “chameleon sequences,” which are stable in either alpha-helix or beta-sheet conformations

Question 17

What goes wrong in pathogenesis of Prion diseases?

Answer 17

The PrPSc prion form of the protein is autocatalytic–it catalyzes the conversion of the normal PrPC protein into new PrPSc protein.

This form is insoluble and resistant to proteolysis, so normal proteases cannot degrade it.

Question 18

What can increased levels of PrPSc cause?

Answer 18

May stimulate apoptosis in CNS (gain of function) and/or loss of function (i.e. loss of normal PrPC may kill cells)

Question 19

How is clusterin involved in prion disease pathogenesis?

Answer 19

Some chaperones like extracellular clusterin inhibit amyloid formation by promoting dissociation of the fibrils, others seem to accelerate it.

Question 20

How does one acquire abnormal prions?

Answer 20

They can arise spontaneously within cells and can also be transmitted from one animal to another.

Question 21

Infectious prions have what characteristics?

Answer 21

1. No detectable nucleic acid
2. Highly resistant to heat and disinfecting agents
3. Resistant to protease degradation
4. Beta-pleated sheets

Question 22

What is the immune response to spongiform encephalopathies?

Answer 22

There’s not one. No detectable immune or inflammatory response.

Question 23

T/F: Scrapie is difficult to transmit between species.

Answer 23

True

Question 24

How do sheep transmit Scrapie?

Answer 24

Spreads within flock by contact of lambs with the placenta and placental fluids of infected ewes

Question 25

What is the most common type of CJD?

Answer 25

Sporadic

Question 26

What did vCJD arise from?

Answer 26

Bovine spongiform encephalopathy

Question 27

What is the proposed pathogenesis of vCJD?

Answer 27

Orally ingested prion proteins are absorbed and transported to the brain primarily by peripheral nerves. Direct penetration into the brain across the blood-brain barrier is conceivable.

Question 28

When and how did bovine spongiform encephalopathy arise?

Answer 28

BSE arose in England in late 1980s from feeding Scrapie-infected (and later, BSE-infected) animal parts to cattle.