Prion Disease Flashcards
What are Prions?
- Protein infection: Prion
- Proteinaceous infectious particle
- An infectious protein – no DNA/RNA
- Replicates by modifying normal cellular proteins
- Aetiology can be genetic, sporadic, or infectious
- There is a specific prion protein (PrP) on human chromosome
20 which is generally the causative agent in prion diseases, but
any protein that causes the misfolding of other proteins can
be referred to as a prion.
How are prions infectious?
- Protein structure is key to its function
- Prions fold in an unusual way – the primary structure is the
same but the secondary/tertiary structure is different - The mis-folded protein then “recruits” the correctly folded
proteins, and converts them to the mis-folded version – this is
how the prion replicates - Prions are resistant to normal sterilisation methods, including
heat, chemical, and ionising radiation
PrP – the prion protein. Explain.
Gene: PRNP – Prion Protein:
* PrPC - Cellular PrP
* PrPSc – Scrapie PrP
* PrPRes – Protease resistant PrP
- PrP is expressed throughout body, highest levels in the brain
- Present in pre- and post-synaptic membranes
- Function not fully clear, potential roles in memory formation
and circadian rhythm - PrPC – more α-helices
- PrPSc – more β-sheets
https://bmcbiol.biomedcentral.com/articles/10.1186/s12915-017-0375-5
https://bmcbiol.biomedcentral.com/articles/10.1186/s12915-017-0375-5
What are prion disease?
- Prion diseases= neurodegenerative disorders caused by prion
proteins - AKA as transmissible spongiform encephalopathy (TME)
- There are several types of prion diseases, each with
differences in presentation - Prion diseases occur in multiple species and can cross the species barrier
- Generally, the mis-folded proteins aggregate, resulting in
neurodegeneration
Check slide 7 for all the disease and which species of animal it relates too.
Why do Kuru and sheep scrapie share the same pathology? (check slide 8 for histological slides)
- Vacuolation
- Neuronal Loss
- Gliosis
- Amyloid deposition
Aetiology of Human prion disease
1 person per million per annum (worldwide)
Sporadic (80-95%)
Clinical syndrome: CJD
Aetiology: ? Somatic mutation Prnp, ? Spontaneous conversion PrPC to PrPSc
Inherited (Familial) (10-15%)
Clinical syndrome: Familial CJD, GSS, FFI
Aetiology: Germline Prno mutation
Acquired (<1%)
Clinical syndrome: Kuru, Iatrogenic CJD, vCJD
Aetiology: Cannibalism, Inoculation, BSE
Routes of entry for acquired prion disease
Recognised transmission routes:
- Corneal &dura mater grafts
- Contaminated EEG electrodes
- Contaminated neurosurgical instruments
- i.m pituitary derived hormones
- Ingestion
Potential transmission routes:
- Airways
- Skin
- Experimental studies
- ? Clinical relevance
Non-PrP Prion Diseases
- There are several examples of prions that do not involve PrP,
some of which are non-pathogenic. - Cytoplasmic polyadenylation element binding (CPEB) – forms
aggregates as part of memory formation - Some examples of prions in fungi
Types of Prion Diseases
- Scrapie
- Bovine Spongiform Encephalitis (BSE) “Mad Cow Disease”
- Creutzfeldt–Jakob disease (CJD)
- sporadic (85%), familial (14%), or acquired (1%)
- Variant CJD (vCJD)
- Fatal Familial Insomnia (FFI)
- Gerstmann-Straussler-Scheinker disease (GSS)
- Kuru
- Variably Protease-Sensitive Prionopathy (VPSPr)
What is Scrapie?
- Affects sheep and goats
- Not thought to be transmissible to humans
- Symptoms 18 months – 5 years after exposure
- Unusual behaviour, weight loss, pruritus (itchy skin), progressive ataxia
(coordination/balance issues) - Pruritus may be where the name originates: the sheep would scrape their skin against rocks and fences -> scrapie
What is Bovine Spongiform Encephalitis?
- “Mad Cow Disease”
- Causes weight loss, behavioural changes, loss of coordination
- Large outbreak in UK spread by contaminated animal feed
- 184,000 cases confirmed in UK,
- Emerged in 1980’s, peak in early 90’s
– 35,000 cases in 1992
– 14,500 cases in 1995
– 2 cases in 2015
– 1 case in 2019
What is Creutzfeldt–Jakob disease (CJD)?
- Most common of the human prion diseases
- Can be sporadic (85%), familial (14%), or acquired (1%)
Sporadic CJD
* Approx 100 cases/year in the UK
* Occurs globally
* Dementia, behavioural abnormalities, ataxia
* Not thought to be “caught” – likely a random misfolding of the
prion into the pathogenic form occurs by chance
* Possibly somatic mutation
* Rapid progression – most cases less than 1 year, mean 6 months
* CJD cases in the UK since 1990: https://www.cjd.ed.ac.uk/sites/default/files/figs.pdf
Familial CJD
* Dominant inheritance
* Around 20 PrP mutations identified
* E200K most common cause
* Presentation identical to sporadic
Acquired CJD – iatrogenic CJD, vCJD
– Iatrogenic CJD cases have mostly been through contaminated
human growth hormone
* Historic – practice for hGH collection changed in 1985
– Can also occur through dura matter grafts, corneal transplant,
and neurosurgery (contaminated equipment). Possibly blood
products.
What is variant CJD? (vCJD)
- vCJD is acquired through ingestion of BSE contaminated meat
- Closely linked to the BSE epidemic in cattle
- 178 cases/deaths in the UK (worldwide 229)
- Cases occurred 1994-2015, peak early 2000s
- More dormant cases? https://www.cjd.ed.ac.uk/sites/default/files/figs.pdf
BSE and vCJD
Cases of both BSE and vCJD decreased rapidly after the start of the 2000 after the sharp increase in the early 90 (BSE cases) and mid 90’s (vJCD cases)
CJD and vCJD
- Age of onset – usually middle age for CJD, mean onset 28 years for vCJD
- Duration – vCJD often over a year, CJD usually just a few months
- Symptoms – vCJD usually psychiatric/behavioural symptoms first, CJD usually memory/movement
