Prions and Protein-Folding Diseases Flashcards
What were the symptoms of Kuru found in the Fore tribe of papau new guinea?
strange walk, slurred speech facial ticks, uncontrollable fits of laugher
death within 6-12 montsh
What did brain autopsy of kuru victims reveal?
minimal inflammation, but formation of plaques and spongiform encephalopathy due to neuronal loss
How did they ultimately prove that kuru was transmitted via canibalism?
they injected homogenized brain tissue from an individual with kuru directly into the brains of chipanzees
2 years later the first symptoms of kuru were reported and neuropathology revealed kuru in their brains
Why did eliminating the practice of cannibalism in the 1960s not completely stop the deaths from kuru immediately?
because there is a really long incubation period for kuru and other prion diseases
What are some things prions ar eable to withstand?
30 min boiling, 60 days freezing, chemicals, dessication for 2 years, intense UV exposure, nuclease digestion, small levels of protease
but sensitive to high levels pf protease
What is the infectious agent in prion diseases?
a mid folded PrPc protein - PrPsc
it’s capable of inducing the same conformational change in other PrPc proteins
what conformational change occurs to form the PrPsc version?
the Helix A alpha helix turns into a beta sheet
the conformation change to form PrPsc results in what tertiary structure?
it makes the PrPsc proteins to stick together in amyloid plaques
Are all PrPsc proteins in the same strain?
No - there are multiple strains that vary in their infectivity
Where is PrPc usually expressed?
It is ubiquitously expressed, but especially in the brain, eyes, spinal cord, skull, vertbral column, tonsils and distal ileum
this is where the PrPsc protein will accumulate the most
What two secondary structures can the amyloid form int he brain?
amyloid fibers forming amyloid plaques
How can you stain amyloid plaques?
with congo red or thioflavin T dye
What cellular repsonse is initiated by the amyloid fibers within the neurons?
triggers the unfolded protein response
this means protein synthesis just shuts down
eventually cell undergoes apotpsosis
What are the 5 etiologies of prion diseases we know of in humans?
- kuru
- Familial Creutzfeldt-Jakob
- Sporadic Creutzfeldt-Jakob (etiology unkown - most common)
- Iatrogenic Creutzfeldt-Jakob (transmitted through cadaver hormones, contaminated surgical equipment, and corneal implants)
- Variant Creutzfeldt-Jakob (from bovine spongiform encephalopathy)
Is familial CJD autosomal dominent or recessive?
dominant
In inherited prion diseases, what gene has the mutation?
PRNP gene - encodes for the PrPc
In laboratory diagnosis of CJD, what will you see on EEG?
periodic sharp wave complexes
in diagnosis of CJD, what will you see in MRI?
high intensity signal in the striatum and linear lesions of the bilateral posterior thalamic nucleus (pulbinar)
What will you see in the CSF of CJD
elevation of protein 14-3-3
it’s used as a marker (but also seen in encephalitis and cerebral infarct)
What laboratory techniques can you use to diagnose CJD?
- western blot for the PrPsc protein after proteinase digestion (this actually helps figure out the strain of PrPsc too)
DNA sequenceing for mutations of the PRNP ene
ELISA to detect PrPsc protein in brain tissue
How can you test the infectivity of a patient’s PrPsc?
inject it into a mouse and watch
What is the current most promising idea for treating prion diseases?
Using a drug to block the phosphorylation of and activation of EIF2-alpha, which is what turns on the unfolded protein response
this means you still get the prion formation, but you keep the cell synthesizing what it needs to survive, so you don’t get the apoptosis and spongiform encephalopathy
What non-human prion disease transferred to humans in the early 1990s?
bovine spongiform encephalopathy (mad cow disease) transferred to humans in England - vCJD
What are some of the ways vCJD differs from fCJD?
it affects you earlier (28 vs 68)
it takes a little longer to kill you after symptoms (14 mo instead of 5 mo)
