Pathology of CJD

Question 1

What are the findings that lead to protein-only hypothesis?

Answer 1

1. No viral particles detectable
2. No significant inflammatory/immunological reactions of the host
3. Deposition of an abnormal protein, often in form of plaques

Question 2

What is infectivity associated with?

Answer 2

Protein deposits

Question 3

What does not inactivate infectivity?

Answer 3

Damage to nucleic acid

Question 4

What abolishes infectivity?

Answer 4

Extraction of the protein fraction

Question 5

What is the Protein-only Hypothesis?

Answer 5

1. Prusiner 1982: the plaque protein is the infectious agents
2. Weissmann 1985: the normal, non-infectious protein (PrPC) is encoded by the ost and is mainly expressed on neurons
3. The infectious prion protein (PrPSC) has the same amino acid composition, but is resistant to proteases and tends to polymerise

Question 6

What are the different types of transmission?

Answer 6

1. Medical procedures
2. Kuru
3. Exogenous PrP is internalised into the cell
4. During internalisation, replication takes place
5. Formation of externally acquired prions - transmitted forms

Question 7

What mutations leads to an exchange of an amino acid and more prone to misfolding?

Answer 7

Specific mutations in the open reading frame of the gene

Question 8

What do abnormal protein form?

Answer 8

Aggregates and essentially clogs up the cell

Question 9

Define prion

Answer 9

Agent of transmissible spongiform encephalopathy (TSE), with unconventional properties. The term does not have structural implications other than a protein is an essential component

Question 10

Define PrPC or PrPsen

Answer 10

The naturally occurring form of the mature PrnP gene product. its presence in a given cell type is necessary but not sufficient for replication of the prion

Question 11

Define PrPSC or PrPres

Answer 11

Abnormal form of the mature PrnP gene product
Partly resistant to digestion by proteinase K
Believed to differ from PrPC conormationally. Often considered to be the transmissible agent or prion

Question 12

What includes the signal peptide?

Answer 12

primary gene products

Question 13

How many achors are there for the glcosylation trees?

Answer 13

3 GPI anchors

Question 14

When are the signal peptides taken off?

Answer 14

When the primary gene product matures

Question 15

What are protein sensitive?

Answer 15

Cellular form of PrP

Question 16

What can be used as an detection for protease?

Answer 16

The misfolded form which has the same primary structure, it is partly resistant to the proteases

Question 17

What are the 3 different types of prion disease?

Answer 17

1. Sporadic forms: Creutzfeld-Jakob Disease
2. Hereditary forms
3. Transmitted forms: human and zoonotic

Question 18

What are examples of hereditary forms?

Answer 18

1. Familial CJD and Gertsmann-Straussler-Scheinker-syndrome

2. Fatal familial insomnia

Question 19

What is an example of transmitted form?

Answer 19

Kuru (ritual cannabalism in New Guinea)
Variant CJD (BSE epidemics)

Question 20

What are medical procedures (Iatrogenic CJD)

Answer 20

1. Contaminated growth hormone
2. Dura mater grafts, cornea grafts
3. Surgical instruments, EEG electrodes

Question 21

What are features of normal cortex?

Answer 21

• Neuronal nuclei and astrocytes

* In between neuropil and consists of dendrites and axons and synapses forming between neurons

Question 22

What are features of CJD?

Answer 22

• Terminal form of CJD
• Neurons are gone
• Form larger cytoplasm

Question 23

What are the GSS phenotypes?

Answer 23

1. P102L

2. P105L

Question 24

What forms a lot of plaques?

Answer 24

A117V

Question 25

What is a stop codon that is not transmissible?

Answer 25

Y145-stop | forms a lot of amyloid

Question 26

Transmission of prion disease I

Answer 26

1. BSE epidemics in the 1980's and 1990's 2. Widespread dietary exposure of the UK population to BSE prions in the late 1980's and early 1990's 3. Emergence of variant CJD in the mid 1990's 4. vCJD prions detectable in the lymphoreticular system (e.g. tonsils, appendix) thought to precede CNS invasion

Question 27

What does different prion strains correlate with?

Answer 27

Different PrPsc glycopatterns 1. Diglycosylated 2. Monoglycosylated 3. Unglycosylated

Question 28

What prion disease are mono-glycosylated dominant?

Answer 28

1. sCJD type 1 and 2 2. ICJD 3. Kuru

Question 29

What are vCJD and BSE prions ?

Answer 29

di-glcosylated dominant

Question 30

What are vCJD distribution in the body?

Answer 30

1. Brain 2. Eyes 3. Sympathetic ganglia 4. Tonsils 5. Lymph nodes 6. Spinal cord 7. Spleen 8. Adrenal 9. Rectum

Question 31

What regions do kuru and sporadic CJD include?

Answer 31

1. Brain | 2. Spinal cord

Question 32

Where do BSE prions settle down?

Answer 32

Lymphoreticular tissues

Question 33

What is spleen important for?

Answer 33

Proportion of the gut including the appendix | appendix is small protusion of gut - contains those lymphoid follicles

Question 34

What resulted in human-human prion transmission?

Answer 34

Fore kinship groups consumed deceased relatives at mortuary feasts

Question 35

Who did Kuru predominantly affect?

Answer 35

Women and children (of both sexes) with only 2% of cases in adult males

Question 36

What is the central clinical feature of Kuru and Iatrogenic CJD?

Answer 36

Progressive cerebellar ataxia

Question 37

What does KURU most closely resemble?

Answer 37

Iatrogenic CJD caused by peripheral administration of contaminated growth hormone

Question 38

How has Transmission of CJD in industrialised countries occured?

Answer 38

Accidental inoculation with human prions as a result of medical and surgical procedures

Question 39

What did more than 200 cases of CJD resulted from?

Answer 39

Treatment with human cadaveric pituitary-derived growth hormone contaminated with prions

Question 40

What do approximately 200 cases of CJD result from?

Answer 40

Transmission through dura mater grafts

Question 41

Transmission of prion diseases: kuru into primates

Answer 41

1. The agent was previously thought to be a slow virus 2. But it had rather unusual biological properties 3. Transmission studies were carried out in primates 4. The findings led to the proposition of the protein only hypothesis