Prion Diseases

Question 1

What are prion diseases clinically characterised by?

Answer 1

Dementia and ataxia.

Question 2

What is another name for prion diseases?

Answer 2

Transmissable spongiform encephalopathies (TSE)

Question 3

What is the inheritance pattern of familial Creutzfeldt-Jakob disease?

Answer 3

Autosomal dominant.

Question 4

Which disease makes up about 15% of all human TSE?

Answer 4

fCJD

Question 5

Give three examples of acquired prion diseases.

Answer 5

Kuru
Iatrogenic Creutzfeldt-Jakob disease (iCJD)
Variant Creutzfeldt-Jakob disease (vCJD)

Question 6

How is iCJD acquired?

Answer 6

Corneal transplant
Stereotactic EEG
Neurosurgery
Dura mater graft
Cadaveric human hormone therapy

Question 7

How is vCJD acquired?

Answer 7

Dietary exposure to BSE

Blood transfusion

Question 8

What are prions composed of?

Answer 8

Modified protein. Normal cellular PRPC is converted into PRPSC through a post translational process during which it acquires a high beta-sheet content.

Question 9

Which symptoms signify the progression of sCJD?

Answer 9

Visual problems, lack of coordination, dementia, ataxia, death.

Question 10

What is the median duration of sCJD?

Answer 10

4 months

Question 11

What is the mean age of death in cases of sCJD?

Answer 11

Late 60s.

Question 12

In which gene is there a mutation in familial CJD?

Answer 12

PRNP

Question 13

What is Gerstmann-Straussler-Scheinker disease?

Answer 13

Inherited human progressive neurodegenerative disease, associated with mutations in prion gene.

Clinical signs can include: dementia, ataxia, extrapyramidal and pyramidal signs.

Patients with some mutations have neurofibrillary tangles.

Question 14

What is fatal familial insomnia (FFI) characterised by?

Answer 14

Severe untreatable insomnia, cognitive disorder, motor system deficits, endocrine manifestations.

Question 15

What is the mean age of onset and typical duration of fatal familial insomnia?

Answer 15

Mean age of onset - 50 years

Typical duration - 7-36 months (mean duratoin - 18 months)

Question 16

What causes FFI?

Answer 16

A point mutation in the 178 codon of the prion protein gene (PRNP)

Question 17

Which polymorphisms affects onset and lethality of FFI?

Answer 17

Polymorphic codon 129.
129 Met/Met is associated with earlier onset and lethality, and more thalamic damage.

Heterozygosity 129 Met/Val is associated with a more prolonged disease and widespread neuropathological damage with cortical spongiosis.

Question 18

What does iatrogenic mean?

Answer 18

Illness caused by medical treatment.

Question 19

What are the most common reasons for iatrogenic illness?

Answer 19

Corneal transplant

Administration of growth hormone/gonadotrophin from infected donor.

Question 20

What is the evidence that BSE is the cause of vCJD?

Answer 20

Strain typing studies in mice found the agents of BSE and vCJD to have identical strain properties, which were different to sporadic CJD.

Question 21

How might people be exposed to BSE?

Answer 21

Bovine CNS material in food.
Occupatinon-related: veterinarians, farmers, abattoir workers, butchers
Medical products including vaccines.

Question 22

Does sCJD or vCJD have a longer duration of illness?

Answer 22

vCJD at 13 months.

sCJD is 4 months

Question 23

Where might peripheral pathogenesis be found in vCJD?

Answer 23

Lymphoid tissue: tonsil, spleen, lymph node, gut
Neural tissue
Blood
Any other tissue where inflammatory process occurs.

Question 24

What is the prion hypothesis?

Answer 24

It states that the misfolded prion protein, rather than virus or bacteria, is responsible for transmission of prion disease.

Question 25

What appears to be important for prion infectivity?

Answer 25

RNA

Question 26

What is the structure of PrPc?

Answer 26

PRNP encodes a 253 amino acid primary translation product.
N-terminus is largely unstructured
C-terminus globular domain containing three alpha-helices and two short beta-pleated sheets
N-linked glycosylation of variable occupancy at Asparagine 181 and 197
The structure is stabilised by a disulfide bridge connecting helices 2 and 3.

Question 27

What is cellular PrP?

Answer 27

It is a naturally occurring glycoprotein with two bulky N-linked glycans attached to asparagines 181 and 197.

Question 28

What are the differences between PrPc and PrPsc?

Answer 28

PrPc: Normal cellular isoform, 3% beta sheet, monomeric, soluble, protease sensitive.

PrPsc: Disease-associated isoform, 43% beta sheet, highly aggregated, insoluble, partially protease resistant.

Question 29

What role do polyanions play in prion infection?

Answer 29

They stimulate prion polymerisation and infectivity.

Question 30

What is the polyanionic template made of?

Answer 30

Can be RNA, glycosaminoglycans, possibly others

Question 31

What is the role for glycosaminoglycans?

Answer 31

At cell membrane surfaces are thought to be the natural templates for prion polymerisation.

Question 32

Where is most prion protein found?

Answer 32

Neuronal plasma membrane, neuronal early and/or recycling endosomes.

Question 33

How were wildtype animals infected from PrPc?

Answer 33

PrPc highly purified from brain.
Only polyanions added (RNA or glycosaminoglycans)
Brain PrPc plus polyanions produce protease-resistant, infectious prion amplification.
Infection of wildtype hamsters achieved at reasonable titre.

Question 34

Which yeast protein converts to a prion form?

Answer 34

Yeast Sup35 protein converts to a prion form called PSI+.

Question 35

What difference does protein conformation make?

Answer 35

It defines prion strain phenotype - different folding states generated at different temperatures gave distinct phenotypes that were heritable.

Question 36

What is the exact nature of the infectious agent?

Answer 36

Structurally altered prion protein, plus lipid cofactors, plus accessory polyanion template (RNA or sulphated glycosaminoglycan).

Question 37

How does agent replication occur?

Answer 37

PrPsc forms oligomers and then fibrils on aminoglycan or RNA polyanions at membranes, incorporates native PrP at fibril termini.

Question 38

Have you done the further reading yet?

Answer 38

What makes a prion infectious? - Supattapone, S.

The propagation of prion-like protein inclusions in neurodegenerative diseases. - Goedert, M et al.