Flashcards in Prions Deck (28)
What was significant about surgical instruments used on CJ-diseased patients?
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!
What is the only certain method of avoiding iatrogenic transmission of CJ-contaminated surgical instruments?
Incineration and discarding of instrument sets
What is PRNP?
Prion protein: a naturally occurring CNS protein encoded by the PRNP gene
What is PrPC?
Cellular prion protein
What is the structure of PrPC?
Structured region at C-terminus
Unstructured region at amino-terminus
What is the "Protein-only" hypothesis and who formulated it?
Stanley Prusiner posited that the prion protein alone, with NO nucleic acids, is responsible for transmissible forms of spongiform encephalopathy.
What is PrPSc?
When a prion protein misfolds, it becomes PrPSc (for "Scrapie"). It accumulates in amyloid plaques in the brain, and causes neurodegeneration (mechanisms unknown).
What are PrPSc fibrils?
When PrPC proteins (alpha-helix) misfold, they form trimers of PrPSc proteins (Beta sheets). When these trimer units stack up, they form fibrils.
What is PrPres?
Largely synonymous for PrPSc. Abnormal, partially protease resistant Prion disease associated isoform of PrP.
What is the autocatalytic model of PrP polymerization?
The conformational conversion of PrPC to PrPres is rare unless catalyzed by contact with an existing PrPres multimer.
What is the noncatalytic model of PrP polymerization?
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.
What molecules are involved in prion replication and prion infectivity?
What does PrPC do normally?
It seems to act in signal transduction primarily in neurites
What is the neurotoxic prion protein fragment?
Amino acids 106-126
What is an ERAD?
Endoplasmic reticulum associated protein
What are amyloidogenic proteins?
Proteins that contain "chameleon sequences," which are stable in either alpha-helix or beta-sheet conformations
What goes wrong in pathogenesis of Prion diseases?
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.
What can increased levels of PrPSc cause?
May stimulate apoptosis in CNS (gain of function) and/or loss of function (i.e. loss of normal PrPC may kill cells)
How is clusterin involved in prion disease pathogenesis?
Some chaperones like extracellular clusterin inhibit amyloid formation by promoting dissociation of the fibrils, others seem to accelerate it.
How does one acquire abnormal prions?
They can arise spontaneously within cells and can also be transmitted from one animal to another.
Infectious prions have what characteristics?
1. No detectable nucleic acid
2. Highly resistant to heat and disinfecting agents
3. Resistant to protease degradation
4. Beta-pleated sheets
What is the immune response to spongiform encephalopathies?
There's not one. No detectable immune or inflammatory response.
T/F: Scrapie is difficult to transmit between species.
How do sheep transmit Scrapie?
Spreads within flock by contact of lambs with the placenta and placental fluids of infected ewes
What is the most common type of CJD?
What did vCJD arise from?
Bovine spongiform encephalopathy
What is the proposed pathogenesis of vCJD?
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.