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 some causes of inherited prion disease?
Mutations in the PRNP gene may make the PrPC more susceptible to transformation to PrPSc
Which prion disease
= dependent on location of polymorphism
Two common alleles encode with methionine or valine at codon 129
= M/V129
= key determinant of susceptibility + age of onset to sporadic and acquired prion disease
How is sCJD classified?
6 major classifications
= based on Met (M) or Val (V) 129 and molecular weight of PrPSc after protease K digestion
Type 1 = 21 kDa
Type 2 = 19 kDa
MM1, MV1, VV1, MM2, MV2, VV2
= have distinct clinical presentation and pathology
MM1 / MV1
= most common subtype (40%)
What are some causes of acquired prion disease?
= acquired forms are rare
vCJD
= only form of human prion disease known to be transmitted directly animal to human
= related to BSE
age profile of vCJD (variant) vs sCJD (sporadic)
= discovered people infected with CJD very young
= lead to discovery of contaminant in blood transfusions
What are the causes of sporadic prion disease?
= somatic mutation in PrP ORF
= RNA editing error
= protein translational error
= spontaneous conversion of PrPc to PrPSc
(e.g. due to ‘mistake’ in protein folding)
= horizontal transmission from other infected individuals of same / different species
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
What are some possible prion treatment targets?
Currently no effective therapies = treatments are symptomatic
= treat dementia, movement disorders, psychiatric symptoms
Prion reduction therapies (experimental)
= Prnp knockdown
= antibodies to prevent prion conversion
= antibodies prevent prion aggregation
= compounds to stabilise prion fibrils
= antibodies or compounds to promote protein clearance
= compounds to interfere with neurotoxicity
EXTRA READING
= also require supportive care
= can do genetic testing on those at high risk
What are Yeast Prions?
New form of ancient inheritance in yeast
Two proteins
= Sup35 + Ure2p
= can exist in either PrPC or PrPSc-like form
= Sup35 - prion = PSI+
= Ure2 - prion = URE3
= prion-like forms can aggregate into amyloid fibres
= prion particles are disseminated to daughter cells during cell division
= protein-based epigenetic elements that modify gene expression in daughter cells
EXTRA READING
= first discovered in Sccharomyces cerevisiae
(involved in gene expression, stress response)
= self-replicating proteins that can adopt alternative, self-propagating confomations
= other e.g. Rnq1, Swi1
= yeast prions non-toxic, do not cause disease (useful model for research)
