Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

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

2. Prion disease in humans and animals Flashcards

You may prefer our related Brainscape-certified flashcards:
AP® Biology flashcards Biology 101 flashcards
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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

Explain sCJD

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

Explain fCJD

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

Explain vCJD

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

Explain iCJD

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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 devooid 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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

What are the aqcuired forms of CJD?

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

How do normal and disease-causing prion proteins differ?

A

Differ by misfolding

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

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

A
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

What is the disease causing polymporhism at PRNP

A
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

Explain the initiatio of pathogenesis of CJD

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

What are the infectious particles in prion disease?

A

Most infectious particles - non-fibrillar particles - small molecules

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
20
Q

Explain prion replication in vitro

A
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
21
Q

Once infected to prions change their strains in patients?

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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
- 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 studie din appendix studies - appendectomy samples examined for PrPSc misfolded protein => some cases had misfolded proteins withour 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 arre - not beneficial for pharma
- clinical symptoms late and idsease 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
- recignised 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
- clincial cases in adukt 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 recignised 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 mojr 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

w Molecular Biology of Disease (8 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions