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Molecular Biology of Disease > Prion disease > Flashcards

Prion disease Flashcards

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1
Q

What is a prion?

A

A protein with pathogenic infectious properties in the brain. They have no nucleic acids.

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2
Q

Properties of prion diseases

A

Rare, fatal, neurodegenerative (creates holes (vacuolation)), cause gliosis (brain inflammation / scarring), long incubation period, no adaptive immune response, resistant to most forms of chemical / physical inactivation, glial (brain immune cell) activation.

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3
Q

What is another term for prion diseases?

A

Transmissible spongiform encephalopathies (TSEs)

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4
Q

What organisms do prion diseases effect?

A

Humans and animals (agricultural, captive and wild)

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5
Q

Which animal would you find scrapie in?

A

Sheep and goats

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6
Q

Which animal would you find bovine spongiform encephalopathy (BSE) in?

A

Cattle - aka mad cow disease

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7
Q

Which animal would you find transmissible mink encephalopathy (TME) in?

A

Mink

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8
Q

Which animal would you find chronic wasting (CWD) disease in?

A

Deer and elk

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9
Q

What does aetiology mean?

A

Cause

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10
Q

Which prion disease are we most concerned will infect humans?

A

CWD

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11
Q

How do prion diseases develop?

A

Prion proteins are post-translationally converted to an infectious form (high beta sheet content) where they are able to form aggregates in the brain.

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12
Q

What are symptoms of prion disease?

A

Dementia, ataxia (poor muscle control), myoclonus (quick jerking movement), sometimes visual abnormalities

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13
Q

When in a patient does Creutzfeldt-Jakob disease usually develop?

A

In their 70s

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14
Q

How are prion diseases transmitted?

A
  • Between individuals of a species
  • Between species (zoonotic)
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15
Q

How big are prion proteins?

A

Sub-viral size

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16
Q

What are prion proteins resistant to?

A

Conventional sterilisation and decontamination methods (autoclave), UV (ionising) radiation, formalin / disinfectants

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17
Q

Normal prion protein notation

A

PrP^c

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18
Q

Infectious prion protein notation

A

PrP^Sc

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19
Q

Can infectious prions pass on their pathogenic properties to the next generation / organism?

A

Yes, despite having no DNA.

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20
Q

Differences between prion strains:

A
  • Clinical and pathological features
  • Rates of disease progression
  • Histology
  • Incubation period
  • PrPSc build up
  • Anatomical distribution of brain lesions
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21
Q

How can we define a prion strain?

A

The prions are stable when inoculated into an animal, and when they are passed to another animal ie they adapt to new species / organisms. They have a stable biological phenotype. Biochemical phenotype can also be taken into account.

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22
Q

Sporadic prion disease examples

A
  • Sporadic Creutzfeldt-Jakob disease (sCJD)
  • Sporadic fatal insomnia (sFI)
  • Variably protease sensitive prionopathy (VPSPr)
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23
Q

What could cause sporadic prion disease?

A

We don’t know but maybe:
- Somatic mutation
- Chance conversion of PrPc to PrPSc

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24
Q

Genetic prion disease examples

A
  • Gerstmann-Straussler-Sheinker disease (GSS)
  • Fatal familial insomnia (FFI)
  • Familial Creutzfeldt-Jakob disease (fCJD)
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25
Q

What causes genetic prion disease?

A

Mutations in the prion protein gene. Each disease a different mutation. They destabilise PrPc

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26
Q

Acquired / infectious prion disease examples:

A
  • Kuru
  • Iatrogenic Creutzfeldt-Jakob disease (iCJD)
  • Variant Creutzfeldt-Jakob disease (vCJD)
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27
Q

What causes acquired prion disease?

A

Eating infected tissue, contaminated surgical equipment

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28
Q

Normal prion protein structure:

A
  • 253 amino acids
  • 22 aa ER signal peptide
  • N-terminus largely unstructured but contains Cu2+ binding region
  • N-terminal glycans allowing movement to golgi and ER
  • 23 aa C-terminal GPI (in membrane) anchor sequence
  • C-terminus globular domain with 3 alpha helices and 2 beta sheets.
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29
Q

Where is prion protein expressed?

A

Cell surface of neuronal cells - attached by GPI anchor.

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30
Q

Prion protein gene (PRNP) properties:

A
  • Single copy gene
  • Human chromosome 20
  • Mammalian, avian and amphibian orthologues
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31
Q

What affects prion disease susceptibility / phenotype?

A

PRNP polymorphisms

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32
Q

Why is there no immune response to prion disease?

A

The same protein is present (not foreign), it is just misfolded.

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33
Q

How does misfolding change PRNP?

A
  • Increased beta sheet composition (3 to 43%)
  • Becomes aggregated instead of monomeric
  • Becomes insoluble instead of soluble
  • Becomes protease resistant instead of sensitive.
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34
Q

How do we do biological strain typing?

A
  • Measure incubation periods
  • Map lesion profile ( distribution of how strain targets the brain)
    THERE CAN STILL BE OTHER PHENOTYPIC VARIATION PRESENT THOUGH.
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35
Q

Theory of BSE origin:

A

Sheep carcasses with scrapie were not properly rendered when creating cattle meal and bone meal (food). Therefore the prion disease passed to cows and other animals.

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36
Q

How do we prevent further BSE spread?

A

Stop using animal based MBM for all livestock.

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37
Q

What are florid plaques?

A

Prion aggregates associated with vCJD.

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38
Q

Differences between sCJD and vCJD:

A
  • shorter life expectancy for vCJD
  • shorter illness duration for sCJD
  • psychiatric features in vCJD
  • rapid dementia in sCJD
  • sensory symptoms in vCJD
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39
Q

Which polymorphism at codon 129 predisposes someone to prion disease?

A

MM

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40
Q

What other codon 129 polymorphisms are possible with sCJD?

A

MV and VV (but less common than MM).

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41
Q

Do prion diseases all produce the same phenotypes?

A

No, different strains can produce slight variations in phenotype.

42
Q

PRNP codon 129 MV polymorphism has what impacts?

A

Affects susceptibility and phenotype

43
Q

What is the largest form prion aggregates take?

A

Prion fibrils

44
Q

What are the most toxic form of prions?

A

Protofibrils / oligomers (14-28 molecules)

45
Q

Which prion strain is a PrPc molecule converted to?

A

Whichever strain of PrPSc it comes into contact with; strains are maintained.

46
Q

Why do we think there might be unknown cofactors involved in prion replication?

A

Heparin, digitonin and some phospholipids enhance PMCA.

47
Q

Where does sCJD originate and infect?

A

The brain - not much leaking elsewhere in the body.

48
Q

Where does vCJD originate and infect?

A

Outside the body (external source) and migrate through various organs e.g. lymph nodes, spleen to the brain.

49
Q

How might prions be able to infect the CNS via the blood?

A

Abnormal blood-brain barrier function.

50
Q

How can prions spread between cells?

A
  • Cell-cell contact and transfer
  • Exosomes
  • Tunneling nanotubes
51
Q

Why might there be a high prevalence of PrPSc but low prevalence of vCJD?

A

There may be only one copy of the mutated protein gene and the person is asymptomatic.

52
Q

What is PMCA used for?

A

Detection of PrPSc - early diagnosis of prion disease e.g. in blood or cerebrospinal fluid.

53
Q

What is RT-QuIC

A

Real-time quaking induced conversion. A diagnostic assay for sCJD (detects prions), but not optimised for vCJD.

54
Q

Advantages to developing therapies for prion diseases:

A
  • Many disease models:
  • Cell free systems
  • Cell culture models
  • Organoid systems
  • Organotypic slice cultures
  • Animal transmission studies
55
Q

Disadvantages to developing therapies for prion diseases:

A
  • Prion diseases are rare.
  • Clinical symptoms occur late in the course of the disease, and are irreversible.
  • Pathogenic agent is a misfolded ‘self’ protein.
56
Q

What treatments have shown promise?

A
  • Doxycycline - disrupted PrPSc aggregates in vitro and had a beneficial effect on sCJD patients (small scale).
  • Passive immunotherapy - mouse monoclonal antibodies to PrPc and PrPSc. Small scale study showed neuropathological changes, but was inconclusive.
57
Q

What are current areas of prion study?

A
  • Replication and pathology
  • Animal TSE zoonotic potential (can animal PrPSc convert human PrPc)
  • Diagnostic tools
  • Detection of misfolded proteins in other neurodegenerative disorders
58
Q

What is RT-QuIC is also being developed for?

A

Detection of alpha synuclein, which aggregates in patients with dementia with Lewy bodies, and Parkinson’s. These are more common than prion diseases.

59
Q

Prion protein properties:

A
  • Insoluble in deterent
  • Form aggregates
  • Protease resistant
60
Q

Which animal prion disease is the prototype for the others?

A

Scrapie

61
Q

What are the origins of prion disease in humans?

A
  • Acquired / infectious
  • Genetic / inherited
  • Sporadic
62
Q

What are the origins of prion disease in animals

A

Only infectious / acquired.

63
Q

How is scrapie transmitted between sheep?

A

Shedding into the environment and close contact between sheep e.g. mothers and lambs.

64
Q

What is the prion hypothesis?

A

The causative agent of TSEs is composed of protein only (no nucleic acid genome).

65
Q

What is the function of PrPc?

A

Unknown but it is expressed in many tissues including brain. Involved in copper binding and myelin maintenance and has antioxidant (neuroprotective) properties.

66
Q

What happens when PrPc is knocked out?

A

Host becomes resistant to prion diseases. No other major effect so other functions must be compensated for.

67
Q

How is spontaneous misfolding of PrPc usually controlled?

A

Corrector proteins, but they only work at low PrPc concentrations.

68
Q

Scrapie factfile:

A
  • Recognised for >200 years
  • Endemic in sheep and goats in many countries worldwide
  • Variable prevalence – can get large outbreaks
  • Most infections acquired around birth
  • Clinical cases in adult sheep 2 – 5 years old (symptoms only appear in adulthood)
  • Symptoms: pruritus (itching), behaviour changes, ataxia, weight loss
69
Q

BSE factfile:

A
  • First recognised as a novel spongiform encephalopathy of cattle in 1986 (UK)
  • Epidemiological evidence suggested a link to the feeding of concentrate feed containing mammalian meat and bone meal (MBM)
  • Little evidence of cattle-to-cattle transmission
  • Clinical cases in adult cattle (4-6 years old)
  • Unusually wide host range – evidence of natural transmission to humans, cats, exotic ungulates and goats
70
Q

CWD factfile:

A
  • First recognised in captive mule deer in Colorado, USA
  • Now widespread in free-ranging and captive cervids (including mule deer, white-tailed deer, wapiti, moose) across North America
  • Efficient horizontal transmission
  • Identified in reindeer in Norway in 2016
  • Subsequently cases found in moose and red deer; some in other Scandinavian countries (Sweden, Finland). Norway’s culling didn’t work.
  • Different from North American cases
71
Q

What other animals are BSE like diseases emerging in?

A

Dromedary camels in Algeria.

72
Q

How do acquired prion diseases get from the gut to the brain?

A

They cross the intestinal barrier and infect the spleen (lymphoid tissue) from the stomach. Follicular dendritic cells (FDCs) in lymphoid tissues are the location of prion replication. These FDCs interact with B cells and transfer the infection to them, where it is then transferred around the body in the blood.

73
Q

What is the primary track of acquired TSEs to the brain?

A

Neural pathways (not blood!)

74
Q

How can scrapie / CWD get to the brain?

A

Lymphatic system, nervous system.

75
Q

How can BSE get to the brain?

A

Only the nervous system (not much spread through lymphatic system).

76
Q

What might indicate how transmissable a TSE may be in a natural setting?

A

Its route into the CNS.

77
Q

Which PRNP mutations lead to the most extreme disease phenotypes?

A

Those that occur in the open reading frame.

78
Q

Which amino acid positions can mutations alter susceptibility to scrapie?

A

136, 154, 171 (usually A, R, Q)

79
Q

Which mutation increases sheep’s susceptibility to scrapie?

A

A136V

80
Q

Which mutation makes sheep highly resistant to scrapie?

A

Q171R

81
Q

What is the hierarchy of scrapie resistance?

A

Resistant - ARR > AHQ > ARQ/ARH > VRQ - susceptible

82
Q

Can we selectively breed for scrapie resistance?

A

Yes - there are different amino acid conformations that alter susceptibility.

83
Q

Do BSE susceptibility mutations occur in the ORF?

A

No.

84
Q

Where do mutations increasing susceptibility to BSE occur?

A

Promoter region (deletion of 23bp) and intron 1 (deletion of 12bp).

85
Q

Where does the mutation increasing resistance to BSE occur?

A

Transcription factor binding site (SNP). Reduces PRNP expression which reduces susceptibility.

86
Q

Are there polymorphisms that confer complete CWD resistance?

A

No

87
Q

Which ORF polymorphisms reduce susceptibility to CWD?

A
  • G96S in white tailed deer
  • S225F in mule deer
88
Q

How can we demonstrate 2 apparently different diseases are caused by the same strain?

A

Infect animals in the lab with the ‘different’ prions and observe incubation period and lesion profile - they will be the same.

89
Q

How do we do molecular / biochemical strain typing?

A
  • Western blots - prions form 3 bands: diglycosylated, monoglycosylated, unglycosylated. Different diseases have different banding patterns / glycosylation fragments
  • Measure stability
  • Measure protease sentitivity
90
Q

What may be the basis of strain variation?

A
  • PrPSc conformation (misfolding)
  • PrPc / PrPSc glycosylation
  • Interactions with other host molecules
  • DNA polymorphisms
  • rate of PrPc turnover
91
Q

Which technique is being used to characterise the differences in structure of fibrils from different strains?

A

Cryo-EM.

92
Q

Why is it important to characterise strains?

A

Different strains have different transmissibility / ability to cross species barriers.
Existing control measures may not be effective against emerging strains.

93
Q

How do we prevent scrapie spread?

A

Selective breeding programme aimed at increasing the frequency of scrapie-resistant and decreasing the frequency of scrapie-susceptible PRNP genotypes in the UK sheep population.

94
Q

Atypical scrapie factfile:

A
  • Initially found in Norway
  • Active surveillance (e.g. slaughterhouse surveys) identified similar cases in most European countries
  • Cases in countries free of ‘classical’ scrapie e.g. NZ
  • Almost all are single cases in flock
95
Q

Atypical scrapie biological profile:

A
  • Often no clinical signs
  • Vacuolation/PrPSc deposition predominantly in cerebellum and cerebral cortex rather than brainstem; no lymphoid tissue replication
  • Additional smaller unglycosylated fragment (10-12 kDa) on Western blot
  • PrPSc unusually sensitive to
    protease digestion
  • Susceptibility associated with PRNP codon 141 polymorphism (AF141RQ)
  • Found in genotypes considered resistant
    to ‘classical’ scrapie
96
Q

Atypical cattle TSEs factfile:

A
  • Older animals identified through active surveillance - longer life expectancy.
  • Raises similar issues to atypical scrapie
97
Q

Atypical cattle TSEs biological profile:

A
  • Significant differences in distribution and nature of brain pathology (more damage to cerebral cortex)
  • Different ratios of di-, mono- and unglycosylated fragments
  • Different molecular weight of unglycosylated fragment
98
Q

What is atypical BSE known as?

A

L type BSE.

99
Q

Atypical CWD factfile:

A
  • CWD cases in moose in Norway/Sweden also appear “atypical”
  • Older animals (>10 years)
  • Distinctive neuropathology
  • No lymphoid tissue involvement
  • Varied glycoform profiles
100
Q

What are issues caused by atypical TSEs?

A
  • Are they new diseases or previously unrecognised?
  • Are they transmissible or spontaneous (sporadic)?
  • Implications for disease control programmes (breeding for resistance may increase susceptibility to these, feed bans)
  • Is there a risk to human health? (and other species)
101
Q

Why might atypical diseases go unrecognised on farms?

A

If they only present themselves in older animals, these animals might have died before we realise they are diseased.

102
Q

How are we trying to control prion diseases?

A
  • Vaccination development
  • Improved decontamination
  • Improved models predicting transmission
  • Better understanding of origins

Molecular Biology of Disease (4 decks)

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