Prions Flashcards
Prions
Objectives:
- Describe the differences between PrPC and PrPSc
- Describe the proposed generation of PrPSc forms from PrPC
- Distinguish the symptoms among CJD, GSS, FFI, and vCJD
- Recognize the three forms of CJD: sporadic, iatrogenic, and familial
- Describe the link of BSE to vCJD
What are prions?
Once referred to as “slow viruses” but this is a misnomer, and Most accept now that prions (infectious proteins) cause TSEs (Transmissible spongiform encephalopathies)
Prolonged incubation periods and filterable causative agents led to theory of “slow viruses”
I.Don’t confuse with progressive neurological disorders caused by conventional viruses. Name some.
Subacute sclerosing panencephalitis: chronic measles infection of children
Progressive post-rubella panencephalitis: chronic rubella infection
AIDS dementia complex: chronic infection of neuronal cells by HIV
Progressive multifocal leukoencephalopathy: chronic JC virus infection
What are Transmissible spongiform encephalopathies (TSEs)?
TSEs are rapidly progressive, invariably fatal dementias that have a long incubation period before the abrupt onset of symptoms
What are some pathological changes seen in TSEs?
multifocal spongiform changes
astrogliosis
neuronal loss
amyloid plaques in some forms
minimal inflammatory reaction
What are some human TSEs?
Kuru
Creutzfeldt-Jakob disease (CJD): sporadic, iatrogenic, or familial
Gerstmann-Straussler-Scheinker disease (GSS)
fatal familial insomnia (FFI)
variant CJD
First experimental demonstration of human transmissibility was of kuru to a primate in 1966
What are some animal TSEs?
scrapie (sheep and goats)
bovine spongiform encephalopathy
chronic wasting disease (elk and deer)
First experimental demonstration of transmissibility was for scrapie in 1936
TSE agent for years was thought to be a “slow virus” because it was known to be filterable (typically indicates a virus) and had a long incubation period. What is different about prions?
However, the agent was extremely resistant to treatments that damage nucleic acids and viruses: radiation, nucleases, proteases, alcohol, formalin.
Now, almost certainly, the agent is known to be a prion (proteinaceous infectious particle)
What is the ‘prion theory’?
1) The prion protein is highly conserved and is encoded by humans and animals
2) It is encoded in a single exon on human chromosome 20, most highly expressed in neurons and lymphocytes
3) the final product is a 209 amino acid glycoprotein that is expressed on the cell surface and is anchored by fatty acid addition
the normal cellular form of prions is termed:
PrPC
What is the function of PrPC?
It’s function is unknown, but it may be involved in signal transduction (prnp0/0 knockout mice show only minor cognitive defects)
shown to inhibit formation of amyloid beta (found in Alzheimer’s) by inhibiting BACE1 activity
What is the disease causing form of prions?
PrPSc
Describe PrPSc
- Can arise spontaneously in sporadic or familial TSEs
- Can be introduced by infection or ingestion
Within an individual, PrPC and PrPSc have the identical amino acid sequence, but:
are folded differently
What do differences in prion folding result in?
differences in folding cause PrPSc to be selectively resistant to proteases
Up to 30 mutations in PrP have been identified to date. What are the implications?
(1) lead to different strains and different susceptibilities
(2) the mutations affect PrP folding stability
(3) the less stable the PrP is, the more quickly death occurs
Again, it is believed that the differences in folding somehow cause the disease state. What does this result in?
(1) leads to formation of PrPSc aggregates (fibrils) inside cells
(2) cell death appears to be through apoptosis, not necrosis
(3) bottomline: don’t know what leads to apoptosis
Note about prion induced disease
Disease symptoms appear to occur in CNS only
- PrPSc is mostly limited to the CNS in many diseases (e.g., BSE)
- In other diseases (e.g., vCJD and CWD), PrPSc can be detected in CNS and lymphoid organs
How is PrPSc synthesized?
PrPC is required for the formation of PrPSc (mice lacking PrP are resistant to prion infection).
it has been proposed that normal cells predominantly contain PrPC, but also a small portion of PrP* (a conformational intermediate of PrPC). PrPSc can act as a template to fold PrP* into the PrPSc (pathogenic) conformation instead of the PrPC conformation (cellular chaperones facilitate the transition of PrP* to PrPSc)
More about prion induced disease
The generation of PrPSc from PrP* leads to a chain reaction that converts more and more of the cell’s PrP into PrPSc and away from PrPC
It is known that a “species barrier” exists in regards to prion inducing disease. Explain
Initial infectivity of a new species is poor but subsequent passage within species is good
The template model for PrPSc biogenesis explains these observations
Summary on prion inducing disease
A fundamental finding of prion work is that a single polypeptide of specific amino acid sequence can assume more than one (PrPC or PrPSc) stable conformation.
One conformation (PrPC) is greatly favored in normal, uninfected cells. Consequently, it is very rare for a pathogenic form to arise spontaneously (this may explain the late onset of sporadic CJD: it takes much time for the rare event to occur; however, an age-dependent somatic mutation cannot be ruled out)
This may also explain why introduction of a PrPSc “seed” in infected cases progresses relatively rapidly to clinical symptoms
More about prions
Most “strains” of prions differ by minor amino acid substitutions
The use of a “template” prion, and not amino acid sequence, dictates the final conformation that is assumed
What is scrapie?
an important experimental system for human TSEs: Scrapie is a subacute, progressive ataxia of sheep and goats. In lambs, infectivity is first found at one year of age in the lymphatic tissues and intestines (suggestive of alimentary tract transmission) and the brain is infected by 2 yo. (Not understood how PrPsc reaches CNS, but follicular dendritic cells may be intermediary)
Subsequent years shows spongiform changes and clinical disease
Most of our understanding of prions comes from scrapie prions that have been transmitted to mice or hamsters
What is Kuru?
Described among the Fore people of Papua New Guinea where kuru means “to tremble with fear” (clinical presentation)
Transmitted by ritual cannibalism (No cases since cannibalism stopped)
What is the most common human TSE?
CJD (but still very rare)- present worldwide with ~1 case/million/yr
What are the three forms of CJD?
Sporadic
Iatrogenic
Familial
How does CJD present?
- dementia
- myoclonus
- cerebellar dysfunction (ataxia)
- end stage features include akinetic mutism
Describe sporadic CJD
This accounts for 85% of all CJD, with an average age of onset at 60 years old, and mean survival time of 5-8 months (80% dead within a year)
What causes sporadic CJD
The exact cause unknown, but may be due to chance conversion of PrPC to PrPSc in a single neuron that sets off a chain reaction
No risk factors have been identified
What things are associated with iatrogenic CJD?
a dural grafts
b. corneal grafts
c. pituitary-derived human growth hormone (major source)
More on iatrogenic CJD
no evidence of transmission through blood (in contrast to vCJD)
Mostly resembles sporadic CJD, but short (1-2 years) incubation period for dural and corneal grafts
Describe familial CJD
This accounts for 10-15% of all CJD causes and is inherited in a AD fashion. Associated with specific mutations in prion protein that appear to facilitate the conversion of PrPC to PrPSc
NOTE: incidence of carriers that develop disease depends upon the specific mutation
When does familial CJD present?
average age of onset is 45-50 years old (younger than sporadic CJD)
What is the mean survival for familial CJD?
2-4 yrs (longer than sporadic CJD)
How is CJD diagnosed?
- suggested by the typical clinical course (rapidly progressive dementia and myoclonus)
- can be confirmed by histological findings of cerebellar spongiform changes, general lack of amyloid plaque
- check CSF to rule out tertiary syphilis or subacute sclerosing panencephalitis
- specific to sporadic CJD: check for characteristic periodic complexes in EEG
What is the MOA of GSS disease?
AD
What causes GSS disease?
Most often associated with a mutation at codon 102 of prion protein
How does GSS disease present? Average age of onset?
Clinical features are heterogeneous, differ from CJD- marked by gait abnormalities and ataxia; dementia is less common
average age of onset is 48
atypical, but no characteristic EEG
What is the prognosis for GSS disease?
mean time to death is 5 years or more
How is the histo of GSS disease unique?
Histopathology differs in that numerous amyloid plaques containing prion protein can be observed in addition to the spongiform changes
What causes FFI disease?
AD disease caused by mutations in codon 129 and 178 of prion proteins
When does FFI disease typically present?
Average at 49yo with a 13 month mean survival time
What are the main clinical features of FFI disease?
Clinical features include sleep disturbances and autonomic dysfunction
Describe the histo of FFI disease
Histopathology reveals much neuronal loss, but rarely spongiform changes or plaques
Variant (v) CJD was first described in Britainn in the 90s. What is it?
Patterns of the protease-resistant form of the pathogenic prion protein confirm that vCJD is the same as BSE (“mad cow disease”)
BSE first reported in UK in 1986 after change in feed-rendering process cattle probably contracted it from scrapie-infected sheep. Feeding subsequent cattle with rendered beef products spread the disease more rapidly by breaking the species barrier
incidence was about 1 in every 10,000 cow
BSE has spread to much of western Europe, Japan. Reported in Canada and US
vCJD transmission is probably through:
the consumption of contaminated beef, but blood transfusions have also been implicated
- FDA bars blood donations from people who have lived in Britain more than 3 months or received a transfusion there since 1979
- FDA bars blood donations from people who have received a transfusion in France since 1980
T or F. vCJD is more contagious than classical CJD
T. higher level of infection in periphery than in classical CJD
In addition to the brain, spinal cord, retina, dorsal root ganglia, and bone marrow, vCJD prions can be detected where?
in tonsils, spleen, lymph nodes, and appendix
What is the average age of onset for vCJD?
29 years with a 14 month survival time (possibly with a 10 year incubation period)
All cases of vCJD thus far are all homozygous for:
methionine at codon 129 of PrP
How does vCJD present?
Characterized by anxiety, depression, sensory abnormalities followed by visual problems and akinetic mutism at the time of death
How is vCJD diagnosed?
- progressive neuropsychiatric disorder of greater than 6 months
- atypical EEG
- prion-positive tonsil biopsy
Histopathology of vCJD disease reveals what?
numerous “florid” (daisy-like) plaques and spongiform changes in basal ganglia
How can TSEs be prevented?
A. Can only offer genetic counseling for familial forms
B. Restrict blood donations
C. Ruminant feed ban, import ban
D. Cull sick animals (“downers”), screen brain tissue with ELISAs
E. Avoid pooled sources for grafts and properly sterilize equipment: soak instruments in 1 N sodium hydroxide for one hour followed by autoclaving at 134 C for one hour
