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w Molecular Biology of Disease > 2. Prion disease in humans and animals > Flashcards

2. Prion disease in humans and animals Flashcards

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1
Q

Desribe prion diseases

A

Prion diseases are:
- rare
- 100% fatal
- in humans, agricultural, captive and wild animals
- Genetic, sporadic and infectious
- Many subtypes
- transmissible spongiform encephalopathies

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2
Q

What is a transmissable spongiform encephalopathy (TSE)?

A

Transmissable spongiform encephalopathy (TSE) - fatal neurodegenerative diseases - caused by abnormal, infectious misfolded proteins - prions - progressive brain damage - sponge-like appearance of affected brain tissue

-> Bovine spongiform encephalopathy (BSE) or “mad cow disease”
-> scrapie in sheep
-> transmissable mink encephalopathy (TME)
-> chronic wasting disease (CWD) - in deer and elk
- Creutzfeldt-Jakob disease (CJD) - human form

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3
Q

Explain Creutzfeldt-Jakob disease (CJD) and its types

A

Creutzfeldt-Jakob disease (CJD) - human form of transmissable spongiform encephalopathy (TSE) - in histology causes holes in brain tissue + accummulation of abnormal prion protein (PrPSc):
- variable phenotypes
- rapidy progressive dementia, ataxia, visual abnormalities
- infectious - transmitted between one species, between species - zoonotic
- long incubation period

  • sporadic CJD (sCJD)
  • genetic CJD (fCJD)
  • variant CJD (vCJD)
  • latrogenic CJD (iCJD)
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4
Q

Explain sCJD

A

Sporadic sCJD:
- Most common form (about 85% of cases)
- Occurs randomly without a clear cause - no evidence that genetic factors play a role
- Typically affects people aged 60+
- The cause of prion misfolding in sporadic CJD is unknown

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5
Q

Explain fCJD

A

Familial (genetic) fCJD:
- An inherited form of the disease
- Caused by mutations in the PRNP gene - polymorphic on the site in ORF, which encodes the prion protein (PrP).
- Family members of affected individuals may also be at risk due to autosomal dominant inheritance
- Accounts for about 10-15% of cases

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6
Q

Explain vCJD

A

Variant vCJD:
- A rare form of CJD linked to the consumption of meat contaminated with prions from BSE
- vCJD typically affects younger people (under 40), whereas sCJD generally affects older adults
- Unlike sporadic CJD, which primarily causes dementia early on, vCJD often begins with psychiatric symptoms, such as depression or anxiety, and progresses to neurological impairment

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7
Q

Explain iCJD

A

iatrogenic iCJD:
- Results from exposure to contaminated medical instruments or tissues, such as in surgeries, organ transplants, or the use of contaminated human growth hormone
- The transmission route is through medical procedures, particularly if prions are introduced into the body through infected tissues

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8
Q

Explain the prion hypothesis

A

Prion hypothesis: “Prions are uncommon infectious pathogens that cause a group of fatal neurodegenerative diseases by an entirely novel mechanism” hypothesised before research

“Prions are transmissible particles that are devoid of nucleic acid and seem to be composed entirely of a modified protein”

Prion hypothesis - the causative agent of TSE is composed of protein only - no nucleic acid genome

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9
Q

What is different between prion strains?

A

Different prion strains - distinct:
- clinical and pathological features
- rates of disease progression
- histology
- PrPSc deposition
- anatomical distribution of brain lesions

Prion strains adapt, members of the same species can have different PRNP alleles

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10
Q

How can different CJD prion strains occur if there are no nucleic acids in prions?

A

Prions don’t have DNA - only protein -> protein structure drives disease, not nucleic acids - disease depends on different protein structures (conformations) - different become post-translationally through post-translational modifications

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11
Q

Explain the mutations in PRNP gene and what they cause

A

Mutations in PRNP gene ORF develop prion disease and can cause:
- fCJD
- Gertsmann-Straussler-Scheinker (GSS) disease
- Fatal familail insomnia (FFI)

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12
Q

What are the aqcuired forms of CJD?

A

Acquired
- iCJD - human -> human, ex. via transplantation
- vCJD - dietary exposure to BSE, resistant to sterilisation
- Kuru - currently eradicated

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13
Q

Describe normal form of prion forming protein

A

Normal form PrPc:
- PRNP gene 253 am.a. product on chrm20
- ER signal peptide
- C-terminal GPI anchor to cell membrane
- N-terminus unstructured, has Cu+2 binding region
- little beta helices
- has attached 2 glycans

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14
Q

How do normal and disease-causing prion proteins differ?

A

Differ by misfolding

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15
Q

What are the normally appearing polymorphisms in PRNP gene in humans?

A
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16
Q

What is the disease causing polymporhism at PRNP

A
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17
Q

Explain the initiation of pathogenesis of CJD

A

Misfolded protein acts as template - if encouters normal - misfolds according to the template

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18
Q

What are the infectious particles in prion disease?

A

Most infectious particles - non-fibrillar particles - small molecules

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19
Q

Explain template directed prion replication

A

Misfolded PrPSc aggregates act as templates for the conversion of normal PrPc protein - when contacts diseased form -> aggregates

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20
Q

Explain prion replication in vitro

A
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21
Q

Once infected do prions change their strains in patients?

A

No, usually strain characteristics are conserved - different PrPSc isoforms in different prion diseases

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22
Q

Molecular classifications of sCJD

A
23
Q

What is the difference of disease spread between sCJD and vCJD?

A

Different paths of neuroinvasion - peripheral pathogenesis into CNS:
- cCJD - centrifugal - brain to other organs
- vCJD - centripetal - other organs to brain

24
Q

What are the routes of acquired prion disease?

A

Prions invade through:
- peripheral nervous system PNS
- lymphoreticular systems
- bloodstream and haematogenous route - in blood-brain barrier (BBB) specialised endothelial cells joined by tight junctions - but prions may still enter via structures with extensive vasculature and lack of normal BBB => but evidence for neuroinvasion is stronger

25
Q

What are the possible prion spread routes on cell to cell level?

A

Prions can spread cell to cell by:
- cell-cell contact
- exosomes
- tunneling nanotubes

26
Q

How has the prevalence of vCJD been studied in the UK?

A

Prevalence of vCJD has been studied in appendix studies - appendectomy samples examined for PrPSc misfolded protein => some cases had misfolded proteins without symptoms - long incubation period

27
Q

What can be used for early detection of prion disease?

A

Early detection can be done by:
- Protein misfolding cyclic amplification (PMCA)
- RT-QuIC

28
Q

What are the challenges and advantages in developing therapies for prion disease?

A

Challenges:
- prion disease rare - not beneficial for pharma
- late clinical symptoms and disease irreversible
- pathogenic prion is a self protein - no immune response
- prions are resistance to sterilisation

Advantages:
- many disease models can be used in research - cell free structures, cell culture models, organoids, organotypic slices, animal models

29
Q

What is the one drug which has been shown effective to some extent in CJD but not confirmed?

A

Doxocycline - disrupt PrPSc aggregates - slow down disease progression - but effects were not reproduced in larger study - doxocycline being trialled to be used as prophylactic for carriers of the mutation of familial insomnia

30
Q

What are the options of targeting prions as treatment?

A
  • Doxocycline - not confirmed but maybe dirsbut prion aggregates
  • Monoclonal Abs targeting normal and misfolded prion forms - still inconclusive
31
Q

Explain what is PMCA

A
32
Q

Learning outcomes (human prions)

A
33
Q

What are the animal prion diseases?

A

Animal prion diseases:
- scrapie
- BSE
- CWD
- TME

34
Q

What are the human prion diseases?

A
35
Q

What are the inter-species relations between TSEs?

A
36
Q

What is the function of normal form of PrP?

A

Not clear, expressed in many tissues - but KO of PRNP gene completely resistant to prion disease

37
Q

Compare normal vs unfolded Pr protein

A
38
Q

Explain scrapie

A

Scrapie:
- known for over 200y
- in sheep and goats
- variable prevalence - can get large outbreaks
- most infectious around birth - long incubation period - cases in 2-5yr old sheep
- recognised form behaviour changes

39
Q

Explain BSE

A

BSE:
- first recognised in 1986
- linked to feeding mammalian meat and bine meal (MBM) - prions don’t sterilise - contaminated with misfoled protein - fed to other animals
- clinical cases in adult cattle - long incubation period
- BSE very wide host range - evidence of transmission to humans, cats, goats, zoo animals

40
Q

Explain CWD

A

CWD:
- first recognised in captive deer in US
- later unrelated CWD appeared in Sweden in reindeer
- spontaneously arises

41
Q

Is BSE still a relevant issue?

A

No, BSE no longer a major issue - but there are new emerging TSEs in animals

42
Q

Explain peripheral pathogenesis of prion disease

A

Peripheral pathogenesis - prion replication in lymphoid tissue -> neuroinvasion and transmissibility of disease

43
Q

Explain specifics of scrapie/CWD peripheral pathogenesis

A
44
Q

Explain specifics of BSE peripheral pathogenesis

A
45
Q

Explain transmissibilities of TSEs

A
46
Q

What leads to susceptibilities to TSEs?

A

Specific variants of polymorphism in PRNP gene at specific codons lead to higher susceptibility to developing TSE

Ex: scrapie

47
Q

How does TSE prion strain typing work in the lab?

A
  • transmission to lab hosts: different incubation periods of diff strains
  • molecular phenotype: protease sensitivity, Western blot
48
Q

How do different TSE prion strains differ?

A

Prion strains differ in:
- PrPSc conformation
- PrPC/PrPSc glycosylation
- interactions with other host molecules

Strain characteristics can be maintained after passage in another species

49
Q

How have polymorphisms in NRP gene been used to protect cattle from forming TSEs?

A

Control of scrapie - selective breeding of polymporhisms with protective function

50
Q

What is the current main concern of TSEs?

A

New forms are emerging spontaneously - atypical forms of known TSEs - not known why

51
Q

Explain classical vs atypical scrapie

A

Atypical scrapie - genetic susceptibility associated with PRNP codon 14 polymorphism

52
Q

Explain classical vs atypical BSE

A
53
Q

What are the remaining questions about TSEs?

A

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