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Flashcards in Prion Disease Deck (20):

What is prion disease?

Prion Disease are transmissible spongiform encephalopathies. They are a series of diseases with common molecular pathology.
• Transmissible factor
• No DNA or RNA involved. This challenged much of the dogma at the time.
• Prion (proteinaceous infectious only)

Prion diseases have a very rapid disease course - cause degeneration to death within 1 year. They can clinically appear similar to other neurodegenerative diseases.


What are the common human prion diseases?

• Creutzfeldt-Jakob disease (CJD) - most common form of prion disease
• Gerstmann-Straüssler-Sheinker syndrome (GSS)
• Fatal familial insomnia (FFI)


What is the epidemiology of prion diseases?

Human prion diseases affect 1-2 cases per million population. Males and females equally affected unlike many other diseases. About 10-15% cases are familial. Age onset average 55-75, same as other degenerative disorders.
• ?accuracy of figures


What are the animal prion diseases?

• Scrapie affects sheep. We've known about scrapie for 200 years. Doesn't appear to cross species barrier
• Bovine spongiform encephalopathy (mad cow disease). Discovered in 1990s. Does cross species barrier.
• Feline spongiform encephalopathy
• Chronic wasting disease in populations of elk
• Transmissible mink encephalopathy


Identify the key neuropathological features of prion diseases

CJD is characterised by:
• Spongiform change (holes in the cortex) - they are vacuoles seen in the cerebral cortex as well as cerebellum.
• Widespread neuronal loss - seen as general atrophy
• Astrogliosis
• Synaptic Loss
• Accumulation of PrP (Prion protein) in amyloid plaques.


What are the clinical features of CJD?

Patients present with progressive dementia. They also have typical EEG changes and motor disturbance.
• Cognitive decline
• Behavioural changes
• Visual dysfunctions
• Motor and ataxic dysfunctions
• Myoclonus
• Akinetic mutsim

Death within a year. Very rapidly progressive, whereas Alzheimer's and Parkinson's takes 10-15 years.


How is CJD investigated?

• Imaging - rapid atrophy.
• Biopsy/ autopsy for diagnosis. However the pathology of prion disease is not stereotypical in it's distribution, so the biopsy may not contain evidence.


What is the aetiology of CJD?

- Sporadic (90%) - a natural spontaneous process
- Genetic (10%) - mutation in PRPN gene
- Iatrogenic - rare - CJD can be physician-induced . This can be by growth hormone from infected individuals, or dural transplants (before synthetic dura was invented).
- Variant - rare - by eating contaminated beef


Describe Gerstmann-Straüssler-Sheinker syndrome (GSS) and Fatal Familial Insomnia (FFI)

Gerstmann-Straüssler-Sheinker syndrome (GSS)
• Autosomal dominant disorder
• Mild dementia
• Mean age of death 50
• Unless most of the genetic variants, this takes a longer course. Duration 4-5 years.

Fatal Familial Insomnia (FFI)
• Autosomal dominant
• Early sleep disturbances
• Neuropsychiatric disease probably caused by lack of sleep
• Late dementia


Describe the prion protein and its functions.

Prion protein (PrPc) is a normal cell surface protein expressed in neurons and glia. Its gene is the PRPN gene on chromosome 20. It has unknown function, but is thought to be associated with:
• Signal transduction
• Vesicle trafficking
• Anti-apoptotic
• ECM interactions
• Heat shock protein
• Chaperone
• Metal binding

Misfolding of PrPc causes fatal neurological disease, yet PrPc is high conserved in mammals, suggesting it exerts beneficial functions preventing it's evolutionary elimination.


What are the different forms of the prion protein?

PrPc represents the normal cellular protein, PrPp is pathological protein, and PrPsc is scrapies. PrPp has an identical peptide sequence to PrPc! PrPp accumulates within cells and in amyloid deposits. It is also resistance to degradation by proteinase K. It is also detectable by ICC.


Describe the risk of CJD conferred by codon 129

Codon 129 of PRNP
• Risk factor
• Polymorphism, can be either Valine or methionine
• Homozygotes i.e. VV or MM at greater risk than heterozygotes VM
• UK frequencies
○ VV 12%
○ MM 37%
○ VM 51%

Variant CJD is only associated with methionine homozygotes. The worry is, we may still be waiting for vCJD to affect those VV homozygotes, and even MV heterozygotes as the disease has long incubation periods, which may depend on codon 129 genotype.


Describe the prion hypothesis

1. PrPc is normally folded into an alpha-helical structure. This is in equilibrium with its unfolded shape.
2. The unfolded PrP is also in equilibrium with a beta-pleated sheet format which is associated with amyloid. There is a huge energy barrier to unfolding of this structure.
3. This Beta-PrP can form an amyloid plaque which is called a PrPp seed as it interacts with other unfolded PrP causing its irreversible propagation.

There are two mechanisms for this conversion into PrPp:
1. Post-translational modification alters conformation - Newly formed PrPp acts as template for autocatalytic conversion.
2. Mutations in prion gene predispose to PrPp conformation


What is the evidence for the prion hypothesis?

Experimental evidence: PrP knockout mice are immune to PrP infection.
• In PrPc knockout mice, if you insert pathological PrPp, the mouse does not develop PrPp
• This means that PrPp somehow interferes with PrPc to cause disease - the pathological protein changes configuration of host protein.


How are different disease strains caused by the prion protein?

Through western-blot analysis it was shown that glycosylation patterns (post-translational modification) of the proteins can produce different peptides. Western-blots showed:
• 3 or 4 bands depending on how many polysaccharide chains attached
• Nature of attached glycan is also important important

Types 1A, 2A and 1+2(A) are associated with sporadic and iatrogenic CJD.
Type 2B is associated with variant 2B
Types 1B, 1A/B, 2A/B are associated with genetic CJD, GSS, FFI


Describe the species barrier of prion disease

[Scott et al., Cell 1989] Transgenic mice expressing hamster PrP (hPrP). Inoculation of transgenic mice or hamsters with hPrP leads to scrapie in 75 days. Inoculation of wild type mice with hPrP does not lead to scrapie.

There is a species specificity in the transmission of scrapies. However this species barrier broke down when it came to beef.


Describe the history and clinical features of vCJD

In 1996 a new variant of CJD called vCJD was linked to eating beef from cows with mad cow disease (BSE). The entire cow population in the UK was killed in the year 2000.
• Sporadic neuropsychiatric disorder
• Patients <45 years old
• Cerebellar ataxia
• Dementia
• Longer duration than CJD
• Linked to BSE - same glycosylation pattern
• Diagnosed at autopsy since 1990
• All 129 MM homozygotes

At the moment there were no cases of vCJD last year. The worry is, we may still be waiting for vCJD to affect those VV homozygotes, and even MV heterozygotes as the disease has long incubation periods, which may depend on codon 129 genotype.


How is it thought PrPc spreads in vCJD?

We're not entirely sure how the PrPp spreads, but proposed mechanisms of spread include:
1. Introduced to lymphatic regions in gut-lumen after being absorbed
○ Protein taken up through gut wall by dendritic cells – then a time of incubation – protein converts normal protein – then travels up via vagus nerve in the brain
○ However, argument against this theory – why do we not have may deposits in medulla near vagus nucleus?
2. Spread via sympathetic spinal cord tracts.
3. Aggregates released from cells, up-taken into other cells and integrated


How is CJD diagnosed in-vivo?

Genetic CJD:
- Blood test - genetic PNRP sequencing

Sporadic CJD:
- Brain biopsy. PrPp detection by immunohistochemistry and immunoblotting.
- Olfactory mucosa brushing
- Cerebrospinal fluid

Variant CJD:
- Tonsil biopsy
- Blood - PrPp ELISA
- Urine PMCA


What are the therapeutic approaches for prion disease?

• Pentosan polysulphate - a Post-exposure prophylaxis to prevent peripheral replication and neuroinvasion
• Ablation of FDCs [Follicular dendritic cells]
• Beta-sheet breaker peptides
• Vaccination?

No proper treatment options, CJD is a terminal illness. Problem is that this disease is so rare that you can’t do clinical trials because you only have like 1 case per year.