Prions Flashcards
What are Transmissible spongiform encephalopathies (TSEs)?
neurodegenerative diseases, always fatal, no available therapies
how are TSE’s transmissible?
experimentally through inoculation
why “spongiform”?
microscopic vacuoles (lesions) in brain tissue are a feature that help identify the disease
what is the infectious agent of TSEs?
prions (type of protein)
What is Scrapie?
- oldest known TSE
- neurodegenerative disease in sheep and goals
- mother to offspring transmission
- not transmissible to humans
What are the types of TSEs? What are the target hosts>
- Scrapie (sheep and goats)
- Bovive spongiform encephalopathy (BSE): mad cow disease
- Creutzfeldt-Jakob Disease (CJD): human
- Kuru: human
- Chronic wasting disease (CWD): large herbivores
TSEswereinitiallythoughttobe caused by
an unidentified “slow” virus (thought that transmissible infections require nucleic acid)
How was it discovered that TSEs were caused by proteins?
- sensitivity to proteases indicates that the scrapie agent contained protein for infectivity
- resistant to inactivation by modification of nucleic acid
Where are prions found?
surface of neurons
What is the “natural” protein that turns to prions?
PrPc (cellular prion protein)
- highly conserved
- function unknown, potentially synaptic function
- not infectious
What is the “infectious form” of prions?
PrPSc
- smallest known infectious agent
- (Scrapie Prion Protein)
- no nucleic acid
why is no immune response evoked for prion PrPSc?
host protein
How is PrPc different from PrPSc?
PrPSc has a structural difference - irreversible shape/conformation change:
- PrPc: alpha helices, PrPSc: beta sheets
- PrPc: soluble, PrPSc: insoluble
- PrPc: PK sensitive, PrPSc: PK resistant
- PrPc: no aggregation, PrPSc: aggregation
what is proteinase k?
protein degrading enzyme to which PrPsc is immune mainly bc insoluble
how does PrPSc spread?
not self-replication (like a bacteria)
PrPc converted to PrPSc
PrPSc is resistant to
procedures that usually inactivate other infectious agents: heat (autoclaving), disinfectants, UV
what are the steps for PrPc to PrPSc conversion?
- PrPc produced by cell and secreted to cell surface
- PrPSc aquired or produced by altered PrPc gene
- PrPc reacts with PrPSc making a heterodimer on cell surface
- PrPc converted to PrPSc
- PrPSc positive feedback loop to convert more PrPc
- PrPSc dimers (2) can also make oligomer with other PrPSc proteins
- PrPSc is taken in by endocytosis but PrPSc accumulates in endosomes since insoluble = not degraded
- PrPSc continuoes to accumulate as endosome contents are transferred to lysosomes
- toxic -> cell death
what occurred in the experiment when healthy mice are injected with brain fluid from Scrapie sheep?
- mice dont get sick bc proteins can’t replicate on their own
the highest concentration of PrPC is in the
brain
accumulation of prions in the brain causes
neuron death (gives spong-like look) = formation of amyloid plaques
what are amyloids?
insoluble fibrous protein aggregates
symptoms of TSEs?
- long clinical period 5+ year exposure
- personality
- change
- psychiatric issue (depression)
- lack of coordination
- involuntary jerking movements, unusual sensations, insomnia, confusion, or memory problems
- severe mental, mobility, language impairment
- death
What gene is PrP encoded by?
prnp gene (host gene)
what are the 3 characteristics of prion disease?
- infectious
- heritable (mutated prnp)
- sporadic (normal prnp becomes mutated)
Modes of transmission from most to least efficient for prions?
- intracerebral
- intravenous
- intraperitoneal
- subcutaneous (under skin)
- intragastric (oral)
1st 3 are experimental settings
What caused Bovine spongiform encephalopathy?
feeding cow remains to live cows
- cow developed sporadic mutation = PrPSc protein fed back into cow
- transmitted to humans by consumption of cow brain or spinal cord
What is the variant Creutzfeldt-Jakob Disease (vCJD)?
- a rare and fatal form of a TSE that affects humans
- linked to the consumption of meat products derived from BSE-infected cattle
What are the 3 types of Creutzfeldt-Jakob Disease (CJD)?
- Sporadic CJD (~85%)
- Hereditary (familial) CJD(~5-15%)
- Iatrogenic CJD (<1%)
What is Sporadic CJD
no known environmental source - mutation generated
what is Hereditary (familial) CJD?
genetic mutation is associated with CJD – confirmed by genetic tests and family history - protein misfolded
What is Iatrogenic CJD?
from a medical procedure such as surgery - source has often been cadaveric dura matter grafts and contaminated neurosurgical equipment
Why do females have higher levels of kuru?
eat brain of person with sporadic mutation of PrPSc
How was resistance acquired to CJD? How was this found out?
PrPc with M129V mutation is resistant to CJD
- found in people exposed to Kuru that surved the epidemic - took 50 yrs to develop Kuru in these people
What is Chronic wasting disease (CWD)? How is it transmitted)
- TSE of mule deer,white tail deer, elk, and moose
- mode of transmission unknown
- transmission to humans is unknown
What was the case of acquiring vCJD in lab?
- 24 yr old prion lab tech handling brain sections from transgenic mice with human prion gene
- skin puncture with forceps
- patient diagnosed 7.5 years after and died 9 years after with vCJD
- diagnosed through prion protein detection in cerebrospinal fluid
what is Alzheimer’s disease? cause?
fatal, progressive and degenerative disease that destroys brain cells
CAUSE: B-amyloid oligomers build up in brain using PrPc receptor for amyloid beta
what is a similarity between Prions and Alzheimers?
both diseases are dementing disorders that involve the deposition of protein aggregates
