Prion Diseases Flashcards
Can you treat Prion diseases?
No, they’re rapidly progressive, fatal and there are no effective treatments
What causes the symptoms of prion diseases?
-Neurological defects due to accumulation of protein plaques and spongiform changes in the brain - similar to other neurodegenerative diseases
What are risk factors for prion diseases?
- Consumption of contaminated meat (vCJD)
- Inheritance of certain mutations in the PRNP gene (fCJD)
- Iatrogenic exposure (iCJD)
How is the infectious prion agent formed?
Through conversion of normal cellular protein (PrPc) into an extremely stable fold (PrPSC) which can misfold additional protein.
What is the difference between AD and CJD?
AD proteins make neurofibrillary tangles while CJD causes amyloid plaque deposits.
What are examples of the human diseases (inc. traumatic brain injury) that cause noninfectious amyloid formation?
AD, Spongiform encephalitis (from type II diabetes), lewy body dementia, Parkinson’s disease, Frontotemporal dementia
How can chronic wasting disease be transmitted?
Prion form can be found in urine, feces, saliva and ground water and can cross BBB
What is the main difference between Classic Spontaneous CJD and vCJD (Bovine Spongiform Encephalopathy)?
Classic - occurs more at older age (av. 68) and progresses more quickly (4-5 months)
vCJD - occurs more at younger age (av. 28) and progresses slower (13-14 months)
What are the microscopic changes seen in CJD?
Double hockey stick in caudate and putamen (light color) and spongiform encephalopathy on slides.
How to test for CJD using: EEG, MRI, CSF, Biochemistry and DNA Sequencing?
EEG - periodic, sharp wave complexes (electrical activity in brain)
MRI - High intensity -putamen/caudate nucleus (hockey stick) or pulvinar thalamic nucleus
CSF - Elevation of protein 14-3- marker of neuronal degeneration
Biochemistry - Western blotting of PrPSC following proteinase digestion
DNA sequencing - Mutation of PRNP gene can be detected by DNA sequencing
No single test to diagnose prion disease, so what do you do?
Rule out other things.
Meningitis (using spinal tap)
Tumor (using CT)
Where does PrPSC replicate?
Spleen and lymph nodes and then its transmitted to brain via peripheral nerves (portal of entry can effect disease phenotype)
What are the inherited prion diseases?
fCJD, Gerstmann-Staussler-Scheinker syndrome, Familial Fatal Insomnia
- Rare, inherited mutation in PRNP gene
- Begins in adulthood and death within 3 years
How is variant (Creutzfeldt-Jakob Disease) transmitted?
Consumption of meat contaminated with Bovine Spongiform Encephalopathy
How is iatrogenic (iCJD) transmitted?
Hormones from cadaver pituitaries, contamination of grafts or surgical instruments, and corneal transplants
How is fCJD (Familial) transmitted?
Large number of mutations in PRNP gene with different disease phenotypes
What are amyloids?
- Protein deposits associated with disease
- Amyloids initiate unfolded protein response and increased vacuolation
What is PrPc (normal PrP) associated with?
Its a ubiquitously expressed glycoprotein involved in cell growth and maintenance.
What infectious agent causes prion diseases?
PrP protein - mutated copy.
- Normal protein misfolds and creates a prion (PrPSC)
- Usually the protein has a bunch of alpha helices but then they make beta sheets
What is special about prions?
They can survive: 30 min boiling, 60 days freezing, strong formaldehyde, carboxylic acid, chloroform, desiccation for 2 years, intense UV exposure, nuclease digestions
- Smaller than a virus
- Sensitive to high levels of proteases
How long can the incubation period be for Kuru?
Over 40 years - people in the tribe were still getting it in the 90s!
Chimp experiments with Kuru:
- Scientists watched chimps for nearly 2 years with no progress
- Then in june 1965 the first symptoms of kuru were recorded: droopy lip
- Monkey put down
What did the brain autopsy of those with Kuru reveal?
Minimal inflammation, formation of plaques and spongiform encephalopathy due to neuronal loss
What is Kuru? (papa new guinea 1957)
“To shake/shiver” or “The laughing death”
- Initial symptoms include strange walk, slurred speech, and uncontrolled fits of laughter
- Once first symptoms occur, death is certain, occurring within 6-12 months
