Prion Diseases Flashcards
What are prion diseases?
= transmissible, neurodegenerative diseases characterised by prolonged incubated period
= associated with transmissible spongiform encephalopathies
symptoms:
= ataxia
= rapidly progressing dementia
= death in few weeks/ years
can be:
= sporadic = no obvious underlying cause
= acquired = contact with infectious agent
= inherited = mutations in prion protein
Examples of prion diseases in animal and humans?
Animals
= scrapie (sheep, goats)
= BSE (bovine spongiform encephalopathy) (cow)
= chronic wasting disease (deer)
= transmissible mink encephalopathy
= feline spongiform encephalopathy
Humans
= kuru
= CJD (Creutzfeldt-Jacob disease)
= GSSS (Gerstmann-Strässler-Scheinker syndrome)
= FFI (Fatal Familial Insomina)
What is Scrapie?
= itching sensation leads to rubbing and scratching of skin = loss of wool
= locomotor disturbances, tremors, fear, aggression
What is BSE (Bovine Spongiform Encephalopathy)?
= mad cow disease
= possibly caused by cattle being fed meat / bone meal contaminated with sheep scrapie
= infectious agent remains viable at high temperatures
What is Kuru?
Kuru = “trembling”
Epidemic in 1950s in Papau New Guinea (200 deaths/year)
= due to ritual cannabilism
= mean incubation = 12 years (up to 50 yrs)
What is CJD (Creutzfeldt-Jakob Disease)?
Incidence = 0.5-1 million / yr
Unknown how it is acquired, no evidence of person-to-person transmission
Has been transmitted by:
= human growth hormone
= corneal transplants
= cerebral electrodes
= dura mater grafts
= blood transfusions
(BSE was transmitted to humans as ‘new variant’ CJD = vCJD / nvCJD)
What are some symptoms of CJD?
= loss of balance and co-ordination
= slurred speech
= vision problems and blindness
= abnormal jerking movements (myotonia)
= progressive loss of mobility
= loss of cognition and memory
= change in personality
(most people with CJD die within a year of symptoms appearing - usually infection caused by immobility)
What are the neuropathological changes in prion diseases?
= vacuolation (spongiform changes) in grey matter / spinal cord
= PrP-positive amyloid plaques + scrapie-associated fibrils (SAF)
= proliferation of astrocytes (gliosis)
= microglial cell activation (no activation of peripheral inflammatory cells)
= depletion of neurons and synapses
What are some unusual properties of the scrapie agent?
= initially thought to be caused by a slow virus
= inoculating brain / CSF from infected sheep into healthy animals = transmitted disease
= agent is unusually resistant to UV / ioning radiation (not a conventional virus)
= resistant to nuclease digestion / chemical procedures that modify nucleic acids
= reistant to heat and autoclaving
= resistant to formaldehyde (persisted on surgical instruments)
THEREFORE
= must be replicating without nucleic acid!
How do prion diseases relate to the central dogma of molecular biology?
Prion diseases go against central dogma
= it is a protein that is having an effect directly
(not nucleic acids)
(EXTRA READING)
How was the prion protein discovered?
Hamsters injected with scrapie
Isolated brain homogenates, did digestion experiments
Identified a 27-30 kDa protein ion infectious fractions
= resistant to digestion by proteinase K
= had rod like structure resembling SFA
= but no nucleic acid
= prion (proteinaceous infectious particle)
PrPC vs. PrPSc?
PrPC
= normal cell-surface glycoprotein
= non-infectious
= secondary structure = mostly α-helices
= easily soluble, digested by proteases
= physiologically role unknown
(may be copper transport, superoxide dismutase-like enzyme function + maintenance of long-term memory)
PrPSc
= scrapie form
= infectious
= same a.a sequence as PrPC
= secondary structure = mostly β-helices
= insoluble, highly resistant to digestion by proteases
= converts PrPC to PrPSc
= forms aggregates
What is the central role of PrP (prion protein) in prion disease?
= infectious fractions contain PrPSc and no other scrapie-specific macromolecule
= PrPC KO mice resistant to scrapie
= Amyloid in brain formed from PrP
= mutations / polymorphisms in PrP gene:
= cause familial CJD, GSSS, FFI in humans
= control incubation period / susceptibility
= cause prion disease in transgenic mice
= infectious prions have been reconstituted from PrP
What are the models of prion replication?
- Interaction between monomers
- Interaction between monomer and fibrilar seed
EXTRA READING
What is the PrP gene (PRNP)?
Located on chromosome 20 in humans
Codes for the cellular prion protein (PrPC)
What are different strains of prions? What is species barrier phenomenon?
Prion strains
= infectious isolates that when transmitted to identical hosts exhibit distinct prion-disease phenotypes
= have different incubation times, histopathological lesion profiles, specific neuronal target areas
= thought to be due to different PrPSc conformation of seeds
The species barrier phenomenon
= EXTRA READING
= difficulty of transmitting prions from one species to another (due to strong sepcies-specificity)
= due to differences in protein sequence between species (different a.a)
= affect ability of prions from one species to interact with and covert PrP of another species
= may result in different clinical presentation, incubation period, neuropathology
e.g. BSE different to vCJD
