Prion Diseases

Question 1

The BSE prion causes degeneration of ….

Answer 1

gray matter in the nervous system

Question 2

Scrapie is a prion disease found in:

Answer 2

sheep, goats

Question 3

Transimissible Mink enceph. is a prion disease found in:

Answer 3

Mink

Question 4

Chronic wasting disease is a prion disease found in:

Answer 4

Cervids

Question 5

Bovine spongiform encephalopathy is a prion disease found in:

Answer 5

cattle

Question 6

Exotic spongiform encephalopathy is a prion disease found in:

Answer 6

nyala, kudu

Question 7

Feline spongiform encephalopathy is a prion disease found in:

Answer 7

cats (domestic and zoo)

Question 8

TSE in non-human primates is an animal prion disease found in:

Answer 8

lemurs

Question 9

Feline Spongiform Encephalopathy histology:

Answer 9

1. Pronounced spongiform alterations seen in the midbrain, thalamus, and hypothalamus and the striatum.
2. Significant diffuse vacuolization and neuronal necrosis.
3. Significant immunostaining for the scrapie prion protein PrPsc
   Basically - vacuolization of gray matter that looks like a sponge

Question 10

Prion Diseases are:

Answer 10

Transmissible Spongiform Encephalopathies (TSEs), highly transmissable, zoonotic, protein based caused by a mutated/refolded form of the prion protein

Question 11

What causes a prion disease?

Answer 11

Mutated/refolded form of the prion protein (PRPsc)

Question 12

What makes the mutant/refolded PrP dangerous?

Answer 12

It is highly resistant to heat, high pressure, and UV light.

Question 13

Is genetic material involved in prion disease?

Answer 13

No! It is strictly a mutated/refolded form of the prion protein

Question 14

Prion diseases are resistant to:

Answer 14

detergents like formaldehyde, ethanol, high ion concentrations, DNAses and RNAses

Question 15

Prion diseases are sensitive to:

Answer 15

1. proteinase K (high concnetrations

2. denaturants (urea, guanidium)

Question 16

What is dependent on the endogenous prion protein PrPc?

Answer 16

seeding, propagation, and toxicity

Question 17

What is PrPc (endogenous prion protein)?

Answer 17

PrPc is a cell surface protein that is anchored to the plasma membrane by a glycosylphophatidylinositol (GPI)-anchor

Question 18

What are the function of PrPc?

Answer 18

still unknown, but thought to:

1. bind copper for copper import, one prion protein can bind up to four copper ions at the end (amino) terminal
2. Cell adhesion and migration

Question 19

Describe the copper import into a cell by PrPc

Answer 19

Normally, prion protein binds two copper ions but when copper is increased it binds four copper ions which causes endocytosis of the prion protein. The vesicle acidifies and takes off two copper ions that are reduced. Then the prion protein is put back onto the cell surface in its normal state, bound to two copper ions.

Question 20

What makes the Spongiform PrP (PrPsc) different from the normal PrPc?

Answer 20

the first alpha helix (H1) is converted into a beta-sheet. This altered PRP can now form aggregates, which forms fibrils.

Question 21

What are the proposed mechanisms by which PrPc is converted to PrPsc?

Answer 21

It is controversial, and several models are proposed: spontaneous, nucleation, template/assisted

Question 22

Describe the spontaneous mechanisms for the conversion of PrPc to PrPsc

Answer 22

Perhaps there is a specific mutation in the protein that can convert it to PrPc to PrPsc

Question 23

Describe the nucleation mechanism for the conversion of PrPc to PrPsc:

Answer 23

An individual gets infected with a PrPsc protein that will bind to the endogenous protein and turn the endogenous protein (PrPs) into an infected protein (PrPsc)

Question 24

Describe the template/assisted mechanism for the conversion of PrPc to PrPsc:

Answer 24

It requires the action of an additional protein (protein X) that binds the prion protein and converts it into an intermediate form. This intermediate form is a lot more susceptible to the degradation of the mutated prion protein and will change into a mutated prion protein once it comes into contact with one.

Question 25

Which mechanisms require you to become infected with a mutated prion protein first to get the disease?

Answer 25

Nucleation mechanism and template/assisted mechanism

Question 26

Describe Spongiform PrP seeding

Answer 26

PrPsc proteins form small oligomers called “seeds”

Question 27

What are seeds of PrPsc proteins?

Answer 27

small oligomers of PrPsc proteins

Question 28

WHat happens to the seeds of PrPsc proteins?

Answer 28

Propagation: the seeds aggregate into amyloid fibers that can breakdown to form more seeds (amplification)

Question 29

Is PrPsc by itself toxic?

Answer 29

No, it seems to require PrPc

Question 30

The combination of PrPc with PrPsc may form:

Answer 30

An ion channel resulting in exictotoxicity, bringing too much calcium into the cell.
The combination of these proteins may also effect existing channels.

Question 31

Why does prion disease affect nervous tissue the most?

Answer 31

Because neurons contain a lot of prion protein inside the cell body.

Question 32

Why is PrPsc toxic?

Answer 32

The prion protein aggregates formed from seeding and propagation can be taken up into endosomes and lysosomes but they somehow have the ability to teleoport outside the lysosome and into the cytoplasm. So we accumulate large aggregates of the PrPsc inside the cell. This inhibits proteosomes in the cell, because all will be focused on digesting these aggregates. Protein syntehsis will get backed up into the ER, causing a build up of misfolded protein inside the ER. Cell death is induced by ER stress.
It can also be toxic by forming ion channels with the endogenous protein and causing excitotoxicity.

Question 33

What could be potential treatments of prion disease?

Answer 33

1. Try to enhance the clearance of PrP aggregates by stimulating autophagy
2. lipid raft disruption because PrPc is found in areas of more cholestrol (lipid rafts)

Question 34

What is gleevec and what role does it play in potential treatment for prion disease?

Answer 34

Gleevec is an anti-cancer agent that stimulates autophagy and clears out the prion proteins inside the cell.

Question 35

What is cyclodextran and what role does it play in potential treatment for prion disease?

Answer 35

It spreads cholestrol out across the cell membrane and decreases areas of congregated cholesterol to decrease the amount of PrPc in a single area. It disrupts lipid rafts and reduces the concentration of PrPc proteins, making it harder for the PrPsc protein to have its negative effects.

Question 36

Is toxicity of the PrPsc dependent or independent on the endogenous PRP?

Answer 36

Toxicity is absolutely DEPENDENT on the endogenous PRP. Without it, the mutated protein would not be harmful.