11 Prions & prion diseases Flashcards by sanaya k

Prion disease is disease caused by ?

an abnormal protein particle that infects brain tissue

How well did you know this?

Not at all

Perfectly

Prion disease = ..1… disease

neurodegenerative

How well did you know this?

Not at all

Perfectly

Prion disease alternatively known as what ?

transmissable spongiform encephalopathy (TSE)

How well did you know this?

Not at all

Perfectly

Sheep prion disease

scrapie

How well did you know this?

Not at all

Perfectly

cow prion disease

bovine spongiform encephalopathy (BSE) or mad cow disease

How well did you know this?

Not at all

Perfectly

deer prion disease

chronic wasting disease (CWD)

How well did you know this?

Not at all

Perfectly

In humans, prion diseases include…

Creutzfeldt-Jakob disease (CJD) and v-CJD
Kuru
Fatal familial insomnia (FFI)
Gerstmann-Straussler-Scheinke syndrome (GSS)

How well did you know this?

Not at all

Perfectly

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)

How well did you know this?

Not at all

Perfectly

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

How well did you know this?

Not at all

Perfectly

Prion diseases can occur via three mechanisms

1) Sporadic (spontaneous) = 85-90%
2) Genetic (familial) = 10-15%
3) Acquired (infectious/transmitted) = 2-5%

How well did you know this?

Not at all

Perfectly

Different forms of prion disease affect different parts of the brain

Prion disease of the cerebral cortex causes what prion disease?

classical CJD

How well did you know this?

Not at all

Perfectly

Different forms of prion disease affect different parts of the brain

Prion disease of the thalamus causes what prion disease?

fatal familial insomnia

How well did you know this?

Not at all

Perfectly

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)

How well did you know this?

Not at all

Perfectly

Different forms of prion disease affect different parts of the brain

Prion disease of the cerebellum causes what prion disease?

kuru

How well did you know this?

Not at all

Perfectly

Characteristic prion pathology ?

spongiform changes
microglia

How well did you know this?

Not at all

Perfectly

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)

How well did you know this?

Not at all

Perfectly

Protein found in prion diseases (TSEs)

Prion proteins

How well did you know this?

Not at all

Perfectly

Protein found in Alzheimer’s disease

Amyloid-beta protein

How well did you know this?

Not at all

Perfectly

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