11 Prions & prion diseases Flashcards
Prion disease is disease caused by ?
an abnormal protein particle that infects brain tissue
Prion disease = ..1… disease
neurodegenerative
Prion disease alternatively known as what ?
transmissable spongiform encephalopathy (TSE)
Sheep prion disease
scrapie
cow prion disease
bovine spongiform encephalopathy (BSE) or mad cow disease
deer prion disease
chronic wasting disease (CWD)
In humans, prion diseases include…
- Creutzfeldt-Jakob disease (CJD) and v-CJD
- Kuru
- Fatal familial insomnia (FFI)
- Gerstmann-Straussler-Scheinke syndrome (GSS)
Symptoms of prion disease
Anxiety & depression
Ataxia (loss of physical coordination)
Memory loss, loss of cognition
Dystonia (muscle spasms)
Incontinence (bowl & urinary)
Inevitably fatal (no cures, only symptomatic treatment)
Characteristics of prion disease which is a neurodegenerative disease
- Neuronal death leading to spongiform appearance of brain
- Proliferation of astrocytes & microglia
- Build up of amyloid plaques (protein aggregates)
- Evidence of oxidative stress
Prion diseases can occur via three mechanisms
1) Sporadic (spontaneous) = 85-90%
2) Genetic (familial) = 10-15%
3) Acquired (infectious/transmitted) = 2-5%
Different forms of prion disease affect different parts of the brain
Prion disease of the cerebral cortex causes what prion disease?
classical CJD
Different forms of prion disease affect different parts of the brain
Prion disease of the thalamus causes what prion disease?
fatal familial insomnia
Different forms of prion disease affect different parts of the brain
Prion disease of the brainstem causes what prion disease?
- scrapie
- BSE
- chronic wasting disease (cwd)
Different forms of prion disease affect different parts of the brain
Prion disease of the cerebellum causes what prion disease?
kuru
Characteristic prion pathology ?
- spongiform changes
- microglia
Amyloid plaques
1. comprised of ?
2. stack up to..
3. clump together…
4. result in …
- protein , B-pleated sheet rich
- protein stack up to make fibrils (fibres)
- clump together to make a plaque
- prion protein (PrP)
Protein found in prion diseases (TSEs)
Prion proteins
Protein found in Alzheimer’s disease
Amyloid-beta protein
Protein found in Parkinson’s disease
Alpha-synuclein
Protein found in Huntington’s disease
Huntingtin
Protein found in Wilson’s disease
Defects in copper metabolism
Protein found in ALS (amylotrophic lateral sclerosis)
defects in superoxide dismutase
which prion diseases are transmissible ?
- kuru
- BSE (mad cow disease)
- v-CJD (variant creutzfeldt Jakob disease)
Evidence that prion diseases are transmissible [SPLIT !]
- Injections of diseased brain tissue into another healthy animal of same species transmits the disease
- Suggests an infectious agent such as a virus BUT no viral evidence has been found in brain extracts
- Treating the brain extracts with agents (e.g., ultraviolet light/nucleases) that destroy nucleic acids does NOT reduce their infectiousness
- This evidence indicates that the infectious agent in the TSEs is a protein
Prion = …. particle ?
proteinaceous infectious
PrP^Sc = ?
scrapie form of the prion protein
Routes of infection of prion disease overall ?
- ingestion (kuru, v-CJD)
- iatrogenic
What are iatrognic routes of infection of prion disease ?
- corneal grafts
- dura mater grafts
- human derived growth hormone injection (hGH)
- experimental transmission in animal models
Describe pathogenesis of prion disease ?
1) Prions detected by immune system (resistant to proteolysis)
2) Prions replicate inside lymphoid tissue (especially follicular dendritic cells) e.g., tonsils, spleen, peyer’s patches, lymph nodes
3) Prions enter the CNS via nerves of the autonomic nervous system (ANS)
Normal cellular from of prion protein ?
PrP^c
Expression of what is essential for disease pathogensis of prions ?
PrP
knockout phenotype shows what ?
distubred sleep aptterns and sensitivity to oxidative stress
Key event in prion disease pathogenesis
Seroconversion of PrPc (normal cellular form of prion protein) to PrPSc
Some features of normal cellular form of prion protein (PrPc)
- GPI anchored (plasma membrane)
- Monomeric
- Protease sensitive
- Binds copper
- Alpha helices present
- Synaptic location
Some features of diseased form of prion protein (PrPSc)
- Extracellular
- Aggregated
- Protease resistant
- No specific copper bound
- High beta sheet content
- Associated with infectivity
- Not easily decontaminated
Conformations of PrPc ?
3 alpha - helices
2 beta-strands
NMR & X-ray
conformations of PrPSc ? [don’t understand question or answer !]
- secondary structure
- beta-strand rich
- model shown
Proposed mechanisms of PrPSc catalysed conversion (2 types of models ?)
1) Template directed refolding model
2) Nucleation dependent polymerisation model (seeding)
Mechanism of neurodegeneration in prion disease
1) PrPSc is cytotoxic - it accumulates in cells causing damage to neurons
2) Excess prion accumulation leads to neurodegeneration
3) MFGE8 secreted by astrocytes - promotes the phagocytosis of apoptotic neurons
4) Microglia clear apoptotic neurons
5) leave ‘gaps’ (sponge like) and protein plaques
How do inherited prion diseases come about?
Mutations destabilise PrPc and make PrPSc more energetically favourable
CJD can occur with no family history of the disease and no known exposure to infectious prions & late-onset.
How do sporadic prion diseases come about?
- A spontaneous somatic mutation may have occurred in one of the prnp genes in a cell
- Normal PrPC protein may have spontaneously converted into the PrPSc form
- Tends to be a susceptibility polymorphism in their prnp genes
Guidance when treating patients with prion disease ?
- perform the intervention in an operating theatre
- schedule at the end of the list, to allow cleaning
- involve the minimum number of personnel required
- protective clothing should be worn
- single-use disposable surgical instruments and equipment used wherever possible
- effective tracking of reusable instruments
Guidance when treating patients with prion disease protective clothing should be worn examples ?
liquid repellent operating gown, over a plastic apron, gloves, mask and goggles, or full-face visor; for symptomatic patients – this protective clothing should be single-use
why should effective tracking of reusable instruments be in place ?
so that instruments can be related to use on a particular patient
Blood & blood product guidance (safety)
Safety measures to reduce any possible risk of spreading v-CJD through blood…
- Withdrawal & recall of any blood components donated by anyone who develops v-CJD & importing plasma from USA
- Removing white blood cells from all blood used for transfusions (leucodepletion)
- Not accepting donations from people who may have received blood transfusion since 1980
- Promote appropriate use of blood, tissues and alternative through NHS
Potential pharmaceutical interventions for prion disease
- Prnp knockdown
- Antibodies prevent prion conversion
- Antibodies prevent prion aggregation
- Compounds interfere with neurotoxicity
