1.1 Human prion diseases

Question 1

Name 3 types of prion disease nosology

Answer 1

Genetic, sporadic and infectious

Question 2

What is another name for prion diseases?

Answer 2

Transmissible spongiform encephalopathies

Question 3

Name clinical manifestations of Creutzfeldt-Jakob disease

Answer 3

Rapidly progressive dementia, ataxia, myoclonus and visual abnormalities

Question 4

Name pathological manifestations of Creutzfeldt-Jakob disease

Answer 4

Neuronal loss, gliosis, spongiform change, accumulation of abnormal prion protein in the brain

Question 5

Name 3 sporadic prion diseases

Answer 5

Sporadic CJD
sporadic fatal insomnia
variably protease sensitive prionopathy

Question 6

Name 3 genetic prion diseases

Answer 6

Familial CJD
Fatal familial insomnia
Gerstmann-Strussler-Scheinker disease

Question 7

Name 3 infectious prion diseases

Answer 7

Variant CJD (dietary exposure to BSE)
Iatrogenic CJD (acquired through medical interventions)
Kuru

Question 8

What clinical features are different between prion strains?

Answer 8

1) Symptoms
2) Rates of disease progression
3) Histology and neuropathology
4) PrP(SC) deposition

Question 9

How many copies does PRNP gene have?

Answer 9

One

Question 10

Which chromosome is PRNP gene found on?

Answer 10

20q

Question 11

How many exons does PRNP gene have?

Answer 11

One

Question 12

What prion disease features are affected by PRNP polymorphisms?

Answer 12

Susceptibility and phenotype

Question 13

How long is the normal PrP protein?

Answer 13

253 amino acids

Question 14

What three motifs does the PrP protein contain?

Answer 14

ER signal peptide (N-terminus), Cu2+ binding octapeptide repeat region (N-terminus), GPI anchor (C-terminus)

Question 15

What is the secondary structure of PrP(C) C-terminus?

Answer 15

3x a-helices, 2x short b-sheets

Question 16

Which PrP residues are N-glycosylated?

Answer 16

Asp181, Asp197

Question 17

What is the function of GPI anchor in PrP(C)

Answer 17

To attach to the membrane at cell surface

Question 18

Which PRNP polymorphism is associated with a significant change in phenotype?

Answer 18

Codon 129: either M or V residue

Question 19

Which codon 129 polymorphism predisposes to CJD?

Answer 19

Homozygous M (MM)

Question 20

What may be two potential causes for the initial PrP misfolding in sporadic CJD?

Answer 20

Somatic mutation

Chance conversion of PrP(C) to PrP(SC)

Question 21

Which other PRNP mutation is affected by and linked with the codon 129 polymorphism?

Answer 21

D178N that causes fatal familial insomnia

Question 22

What form of PrP(SC) aggregates is most infectious?

Answer 22

Non-fibrillar, short oligomers of 14-28 PrP molecules

Question 23

What is the pathogenetic function of the Asp glycans when the PrP(SC) fibrils form?

Answer 23

Distortion of the membrane

Question 24

What technique is used for detecting low amounts of abnormal PrP?

Answer 24

Protein misfolding cyclic amplification: PMCA

Question 25

What is the basis of PMCA?

Answer 25

Cell lysate is blasted with an ultrasound sonicator to break up aggregates into smaller proteins, thus providing more and more seeds for abnormal fibrils to grow. If they appear, that indicates presence of an abnormal protein in the initial sample

Question 26

What molecular features are used to classify prion strains?

Answer 26

1) Size of protease resistant bands on Western blot
2) Codon 129 polymorphism
3) Asp residue glycoform ratio

Question 27

How do prions invade the brain in acquired disease?

Answer 27

Prions replicate in peripheral organs (spleen, lymph nodes), which are directly innervated by CNS neurons that can become infected

Question 28

What is the haematogenous route of prion invasion?

Answer 28

Prions invade the blood, then cross into the CNS through weak points in the BBB

Question 29

What 3 routes allow cell-cell spread of prion proteins?

Answer 29

Direct contact and transfer
Exosome vesicles
Nanotubes