Week 1: Transmissible Spongiforms Encephalopathies (Prion stuff)

Question 1

BSE and its history with viruses

Answer 1

• BSE was originally considered to be a viral disease, but was then found to be prions

Question 2

Prions

Answer 2

• Prions are a self-replicating protein that can change shape, which can then cause disease
• Prions don’t follow the replication dogma of DNA -> RNA -> Protein
• Prion genes are in fact highly conserved that has been gained through the evolution
• Under high pressures, a protein fold can bind to itself to create amyloid proteins
• Prion diseases are questionable between gain/loss of function , since proteins are tehcnically always active in some way, therefore it’s mostly agreed that there is a gain of function om the protein

Question 3

The BSE epidemic

Answer 3

• Caused from animals eating contaminated feed, whichw as then banned, causing a decline in cases after the feed was finally exhasuted, but still made its way into human populations
• This disease has existed for a while, however was present in other forms ie Scrapie, TME, CWD, Kuru, CJD etc
• A lot of these cases are likely to be linke dot the original source of contaminated food, but a genetic component is still necessary for disease

Question 4

Scrapie

Answer 4

• Transmitted through milk + urine, accentuated by inflammation
• Naturally occuring disease in sheep
• Incidence related to breed, where some breeds are more resistant than others
• Always fatal as the prion is able to adapt to the host

Question 5

Symptoms of scrapie

Answer 5

• Scratching
• Biting
• Rubbing of the skin
• Patchy loss of wool
• Tremors
• Loss of weight
• Hindquarter weakness
• Imparied vision in some

Question 6

Creutzfeldt-Jakob Disease (CJD)

Answer 6

• 1 case per million worldwide
• Average age of typical CJD is 56 years old, with 4-15% of cases having a familial connection with other cases + 90% of cases ending in death within 1 year onset
• Can be transmitted by unclean surgical tools previously used to CJD patients
• Increased incidence in certain population demographics
• CJD + other TSEs results in brain tissue being positive for Scrapie-Associated Fibrils (SAFs)

Question 7

The 3 traditional forms of CJD

Answer 7

• Sporadic CJD
• Iatrogenic CJD
• Inherited CJD
• But more recently new forms have arrived: nvCJD + vCJD

Question 8

Kuru

Answer 8

• Found in Okapa district Fore tribe that practiced ritual cannibalsim
• Occured more often in women who were left to eat brains

Question 9

Gerstmann-Straussler-Scheinker (GSS) disease

Answer 9

• A rare autosomal dominant condition in families
• Similar to CJD, but has an extended onset + duration + many amyloid plaques present
• PrP codon-102 changes from proline to leucine, with this change being associated with GSS

Question 10

Fatal Familial Insomnia (FFI)

Answer 10

• A hereditary prion disease that usually presents with symptoms ie inattention, sleep loss + motor signs
• Brain dysfunction preferentially occurs around thalamus region
• FFI is linked to a missense mutation at codon 178 of PrP

Question 11

Infection models to find the causative agent

Answer 11

• Mice and hamsters were injected with grinded neuronal tissues, then infected
• Would take 3/4 of a year for the rodents to be killed
• From autopsies, brain + spinal cord contained the highest tires of prions, being ~ 10^9.5 ID50/g
• Theorised that upon consumption, prions can use the vasculature and neuronal vasculature to then travel to the brain
• Lower titres (10^6ID50/g) were present in the spleen + lymporeticular system
• Prp-KO mice models show that Prp is not essential + are resistant to scrapie, but develop abnormal behaviours after 7 months
• It is thought that PrPc functions for peripheral myelin maintenance + among more

Question 12

Species-specificity of prions

Answer 12

• Unlike many viruses, prionoid properties can change dramatically when passed from 1 species to another
• Properties manifested by prion strains ie incubation times + neuropathology profiles seem to be enciphered some way
• Properties of Prp were different in normal + infected possibly by post-translational events, depsite the gene between healthy and infected not differing
• PrPsc is insoluble

Question 13

Detecting PrPsc

Answer 13

For human TSE diagnosis:
- Immunhistochemistry
- NaPTA precipitation + Western Blotting
For animal TSE diagnosis, but may be useful for humans:
- Bioassays
- Conformation-dependent immunoassay
- Scrapie Cell Assay
Newer assays include Protein Misfolding Cyclic Assay (PMCA) and Real Time Quaking-Induced Conversion (RT-QuIC)

Question 14

Investigations in infefction + pathogenesis via models

Answer 14

• SCID mice are resistant to prions, confirming the importance of the lymphoid system
• PrPo/o mice carrying PrP+/+ brain grafts can develop pathology following an intracerebral injection but only in the graft
• PrPo/o mice + graft + reconstituted PrP++ lymphoreticular system (LRS) are still resistant to peripheral prion challenge
• Follicular dendritic cells have been shown to be the required missing cell type for the development of the disease following infection from a peripheral route

Question 15

Routes of infection + secretion of scrapie

Answer 15

Infection:
- Inhalation
- Ingestion of contaminated food/pasture
- Lesions to skin/mucous membranes
- In utero transmission to developing foetus
Transmission:
- Nasal secretions
- Saliva
- Secretion in milk + colostrum
- Excretion via faeces + urine
- Contamination of environment with placenta + other gestational tissues or fluids