Prion Diseases Flashcards
What are prion diseases clinically characterised by?
Dementia and ataxia.
What is another name for prion diseases?
Transmissable spongiform encephalopathies (TSE)
What is the inheritance pattern of familial Creutzfeldt-Jakob disease?
Autosomal dominant.
Which disease makes up about 15% of all human TSE?
fCJD
Give three examples of acquired prion diseases.
Kuru
Iatrogenic Creutzfeldt-Jakob disease (iCJD)
Variant Creutzfeldt-Jakob disease (vCJD)
How is iCJD acquired?
Corneal transplant Stereotactic EEG Neurosurgery Dura mater graft Cadaveric human hormone therapy
How is vCJD acquired?
Dietary exposure to BSE
Blood transfusion
What are prions composed of?
Modified protein. Normal cellular PRPC is converted into PRPSC through a post translational process during which it acquires a high beta-sheet content.
Which symptoms signify the progression of sCJD?
Visual problems, lack of coordination, dementia, ataxia, death.
What is the median duration of sCJD?
4 months
What is the mean age of death in cases of sCJD?
Late 60s.
In which gene is there a mutation in familial CJD?
PRNP
What is Gerstmann-Straussler-Scheinker disease?
Inherited human progressive neurodegenerative disease, associated with mutations in prion gene.
Clinical signs can include: dementia, ataxia, extrapyramidal and pyramidal signs.
Patients with some mutations have neurofibrillary tangles.
What is fatal familial insomnia (FFI) characterised by?
Severe untreatable insomnia, cognitive disorder, motor system deficits, endocrine manifestations.
What is the mean age of onset and typical duration of fatal familial insomnia?
Mean age of onset - 50 years
Typical duration - 7-36 months (mean duratoin - 18 months)
What causes FFI?
A point mutation in the 178 codon of the prion protein gene (PRNP)
Which polymorphisms affects onset and lethality of FFI?
Polymorphic codon 129.
129 Met/Met is associated with earlier onset and lethality, and more thalamic damage.
Heterozygosity 129 Met/Val is associated with a more prolonged disease and widespread neuropathological damage with cortical spongiosis.
What does iatrogenic mean?
Illness caused by medical treatment.
What are the most common reasons for iatrogenic illness?
Corneal transplant
Administration of growth hormone/gonadotrophin from infected donor.
What is the evidence that BSE is the cause of vCJD?
Strain typing studies in mice found the agents of BSE and vCJD to have identical strain properties, which were different to sporadic CJD.
How might people be exposed to BSE?
Bovine CNS material in food.
Occupatinon-related: veterinarians, farmers, abattoir workers, butchers
Medical products including vaccines.
Does sCJD or vCJD have a longer duration of illness?
vCJD at 13 months.
sCJD is 4 months
Where might peripheral pathogenesis be found in vCJD?
Lymphoid tissue: tonsil, spleen, lymph node, gut
Neural tissue
Blood
Any other tissue where inflammatory process occurs.
What is the prion hypothesis?
It states that the misfolded prion protein, rather than virus or bacteria, is responsible for transmission of prion disease.
What appears to be important for prion infectivity?
RNA
What is the structure of PrPc?
PRNP encodes a 253 amino acid primary translation product.
N-terminus is largely unstructured
C-terminus globular domain containing three alpha-helices and two short beta-pleated sheets
N-linked glycosylation of variable occupancy at Asparagine 181 and 197
The structure is stabilised by a disulfide bridge connecting helices 2 and 3.
What is cellular PrP?
It is a naturally occurring glycoprotein with two bulky N-linked glycans attached to asparagines 181 and 197.
What are the differences between PrPc and PrPsc?
PrPc: Normal cellular isoform, 3% beta sheet, monomeric, soluble, protease sensitive.
PrPsc: Disease-associated isoform, 43% beta sheet, highly aggregated, insoluble, partially protease resistant.
What role do polyanions play in prion infection?
They stimulate prion polymerisation and infectivity.
What is the polyanionic template made of?
Can be RNA, glycosaminoglycans, possibly others
What is the role for glycosaminoglycans?
At cell membrane surfaces are thought to be the natural templates for prion polymerisation.
Where is most prion protein found?
Neuronal plasma membrane, neuronal early and/or recycling endosomes.
How were wildtype animals infected from PrPc?
PrPc highly purified from brain.
Only polyanions added (RNA or glycosaminoglycans)
Brain PrPc plus polyanions produce protease-resistant, infectious prion amplification.
Infection of wildtype hamsters achieved at reasonable titre.
Which yeast protein converts to a prion form?
Yeast Sup35 protein converts to a prion form called PSI+.
What difference does protein conformation make?
It defines prion strain phenotype - different folding states generated at different temperatures gave distinct phenotypes that were heritable.
What is the exact nature of the infectious agent?
Structurally altered prion protein, plus lipid cofactors, plus accessory polyanion template (RNA or sulphated glycosaminoglycan).
How does agent replication occur?
PrPsc forms oligomers and then fibrils on aminoglycan or RNA polyanions at membranes, incorporates native PrP at fibril termini.
Have you done the further reading yet?
What makes a prion infectious? - Supattapone, S.
The propagation of prion-like protein inclusions in neurodegenerative diseases. - Goedert, M et al.
