Prions Flashcards
What agent is responsible for transmissible spongiform encephalopathies (TSE)?
Prions
What pathology’s are associated with TSE?
Multifocal spongiform changes, Astrogliosis, Neuronal loss, Amyloid plaques in some forms and
Minimal inflammatory response
TSE is typically characterized by
Long incubation period, but then rapidly progressive. Invariably fatal dementia
What is the prion theory?
TSE agents are extremely resistant to treatments that damage nucleic acids and viruses. TSE agents are now believed to be proteinaceous infectious particles, “prions”
What are the four characteristics of prion proteins?
- Highly conserved among humans and various animals
- Encoded in a single exon on human chromosome 20
- Highly expressed in neurons and lymphocytes
- Final product is a 209 amino acid glycoprotein that is anchored to cell surfaces by a fatty acid
What are the two forms of prions?
Normal is PrPc and Pathogenic form is PrPsc or PrPes
Can PrPc and PrPsc have identical sequence?
Yes but they can fold differently
What are the characteristics of PrPsc’s altered folding?
Unusually stable, only partially degraded by proteases
Aggregates in the cytoplasm of cells
Leads to apoptosis of neurons, but disease mechanism is not understood
Must PrPc be expressed to contract disease?
You betcha
What’s scrapie?
A subacute, progressive ataxia of sheep
First found at one year of age in lymphatic tissues and intestines
By two years of age, brain is infected, followed by spongiform changes and clinical disease
Not understood how PrPsc reaches CNS, but follicular dendritic cells may be intermediary
What’s KURU?
First documented human TSE. Transmitted by ritual cannibalism. No cases since cannibalism stopped
What’s the most common human TSE?
CJD. It’s extremely rare
What are the clinical features of CJD?
Dementia, Myoclonus, Ataxia, and Mutism near death
What are the characteristics of sporadic CJD?
85% of all CJD Average age of onset is 60 years Mean survival time is 5-8 months No risk factors have been identified Exact cause unknown, possibly a chance conversion of PrPC to PrPSc?
What sources have been documented as transmitting iatrogenic CJD?
Dural grafts, corneal grafts, and human growth hormone. No convincing evidence of blood transmission
Does iatrogenic or sporadic CJD have a shorter incubation period?
Shorter incubation period (1-2 years) for dural and corneal grafts than for sporadic CJD
What are the characteristics of familial CJD?
15% of total CJD Autosomal dominant pattern Associated with specific alterations in PrP Average age of onset is 45-50 years old Mean survival time is 2-4 years
What Sx suggest CJD?
Rapidly progressive dementia and Myoclonus
How do you confirm CJD?
Confirm by histology: cerebral spongiform changes
and general lack of amyloid plaques. Check CSF to rule out tertiary syphilis or SSPE
(Specific to the sporadic form: Characteristic periodic complexes in EEG)
What are the characteristics of GSS dz?
Autosomal dominance pattern
Most often associated with a mutation at codon 102 of PrP
What are the clinical feature of GSS?
Clinical features are variable, differ from CJD Average age onset is 48 Mean time to death is 5 years or more Gait abnormalities and ataxia Dementia is less common, may occur late
Diagnostic features of GSS?
No characteristic EEG
Amyloid plaques in addition to spongiform changes
What are the characteristics of FFI?
Autosomal dominant pattern
Mutations at codons 129 and 178 of PrP
What are the clinical features of FFI?
Average age onset is 49, 13 months to death
Clinical features
Sleep disturbances
Autonomic dysfunction
What histologic features do you see with FFI?
Histopathology reveals much neuronal loss, but rarely spongiform changes
What’s variant CJD?
First reported in UK in the 90s. Patterns of the protease-resistant form of PrP confirmed vCJD is the same as BSE
How does transmission of vCJD occur?
Through ingestion of contaminated beef and blood transfusions
What are infectious sources of vCJD?
Brain, spinal cord, retina, DRG, bone marrow, tonsils, spleen, lymph nodes, appendix and blood
What are the clinical features of vCJD?
Average age onset is 29 years with 14 month mean survival time. Sx= anxiety, depression and sensory abnormalities. Visual problems late and akinetic mutism at death
Have all victims of vCJD been homozygous for methionine at position 129 of PrP?
Yes
Dx of CJD?
Progressive neuropsychiatric disorder of more than 6 months. Atypical EEG without periodicity. Prion-positive tonsil biopsy. Histology reveals florid plaques and spongiform changes in basal ganglia
What can you do to prevent TSE?
- Genetic counseling for familial forms
- Ruminant feed ban, import ban
- Cull sick animals, screen brain tissue with ELISAs
- Avoid pooled sources of grafts and properly sterilize equipment
- Soak instruments in 1 N sodium hydroxide for one hour followed by autoclaving at 134 C for one hour
- Restrict blood donations
Can a single PrP of specific amino acid sequence assume more than one conformation?
Yes.
One conformation (PrPc) is greatly favored in an uninfected. Do spontaneously pathogenic forms commonly occur?
No: a spontaneous pathogenic form is very rare, hence late onset of sporadic CJD
True or false, most PrP “strains” differ by minor amino acid substitutions which dictate final conformation?
True
True or false, a “template” PrP propagates the final conformation?
True
Is there believed to be a species barrier with prions?
Yep
