Prions

Question 1

Examples of prions

Answer 1

-fore
-kuru
-mad cows
-CDJ

Question 2

who discovered Kuru

Answer 2

Carleton GaJdusek

Question 3

Who have Kuru and where are they from

Answer 3

Papua, New Guinea and it is the fore people

Question 4

What is Kuru

Answer 4

-KURU - Disease known since early 1900’s
“Kuru” in Fore language → “Shivering”
-Disease progression:
Uncontrollable muscular twitching
Decreased muscular coordination
(Cerebellar ataxia)
Decreased ability to walk
Use of sticks as crutches
-Dementia
Disease also known as “Laughing Illness”
Progression to muscle atrophy and paralysis
Death

Question 5

What is interesting about Kuru brains

Answer 5

they have these huge vacuoles
-Vacuolar spongiform degeneration of neurons
“Kuru” plaques
No inflammation

Question 6

Which virus is CJD similar to

Answer 6

Kuru

Question 7

CJD

Answer 7

-A rare sporadic disease of the elderly worldwide
-Incidence 1 per 2,000,000 population per year
i.e. expect about 4 cases per year in Quebec
(population 7,500,000
-Also very similar to 2 genetic syndromes:
Gerstmann-Straussler-Scheinker Syndrome (GSS)
Fatal Familial Insomnia (FFI)
-Familial lineages with very high incidence within families of spongiform encephalopathy

Question 8

Pourcentage of people getting kuru

Answer 8

Incidence approaching 40% in affected villages
50% of male and female children
60% of adult women
3% of adult males

Question 9

True or false: Kuru was easily isolated

Answer 9

FALSEEE
They tried to inject kuru brains into chimps and they could not get anything

Question 10

Scrapie

Answer 10

Scrapie:
-contageous disease
caused
- trembling
- ataxia
- weakness
- strange behavior
- ultimately leading to paralysis and death
Histopathology:
- spongiform encephalopathy without inflammation
- kuru plaques and microfibrillar arrays

Question 11

True or false scrapie is a non contageous disease

Answer 11

False
-flock which has never been exposed will never
develop the disease
-But if an infected sheep were put into an uninfected flock
-Then all animals in the flock would develop the disease
- only after a 2-5 year incubation period!
-So, Gajdusek telegraphed Australia to check on the chimpanzees from his original brain inoculations
-They were all trembling and badly coordinated
-Their brains showed spongiform encephalopathy!

Question 12

How did scientists made it work to study kuru

Answer 12

a guy at ucsf inoculated scrapie brain tissue in hamsters and they developed symptoms 30-35 days after inoculation

Question 13

what did scientits find while studying scrapie brains sds page

Answer 13

-Prusiner fractionated infected brain tissue and assayed it for infectivity
-Infectivity was concentrated in membrane associated fractions
-Analyzing these tissue fractions on SDS-PAGE gels
He found that infected sheep brains contained a protein band that was not present in the uninfected sheep brains
-Similar findings were found in all cases of spongiform encephalopathy in Kuru, CJD, scrapie, etc.

Question 14

True or false: treatments that affect scrapie were tratments that inactivated nucleic acids?

Answer 14

falseeeee it was treatments that inactivate proteins
Chemical denaturants (alkali, phenol, SDS, etc.)
Proteases

Question 15

Treatments that inactivate nucleic acid

Answer 15

UV light
psoralens
X-irradiation
DNAse

Question 16

what are prions

Answer 16

an infectuous agen consisting entirely of proteins
at first scientists hated that shit

Question 17

What is prp

Answer 17

-scrapie prion protein
-To everyone’s surprise, PrP was encoded by a host cell mammalian gene (now called the PrP gene)
-Constitutively expressed as a membrane protein in:
Neurons, lymphocytes, follicular dendritic cells, intestinal epithelium and many other tissues
-Function of the PrP gene is unknown

Question 18

Proteinase K treatment of:

Answer 18

(1) PrPsc leaves a proteinase-resistant core PrP 27-30 fragment
(2) PrPc is completely digested

Question 19

Why does PrPsc differs from PrPc

Answer 19

Because of different post-translational modifications:
-they cause radical changes in 3d folding and physical properties
(a) glycosylation at an additional two sites unused in PrPc
(b) removal of the amino-terminal signal peptide sequence
(c) removal of a carboxy-terminal hydrophobic segment
(d) addition of a C-terminal phosphatidylinositol glycolipid
(e) removal of a variable number of
non-signal amino-terminal amino acid residues

Question 20

Dramatic conformational difference in the PrP forms

Answer 20

-alpha helical content of PrPc 40%,
little or no beta sheet
-alpha helical content of PrPsc 20% alpha helix,
50% beta sheet

Question 21

The sum of the changes in prpc

Answer 21

-PrPc is a soluble protein
-PrPsc is stubbornly insoluble
-Localizing in aggregates in infected brain making the brain vacuoles

Question 22

PRUSINER’S STATEMENT OF THE PRION HYPOTHESIS:

Answer 22

A misfolded form of a protein
This form can then catalyze the refolding of other native
molecules into the same distinct “misfolded” conformation

Question 23

prp happy state

Answer 23

alpha helical

Question 24

how to get prpsc

Answer 24

-spontaneous conversion: sporadic
-aquired conversion
-germline mutation, spontaneous conversion more likely: inherited
-somatic mutation, spontaneous conversion more likely: sporadic

Question 25

true or false prions: disease caused by germline mutation 1 may differ from what caused by germline mutation 2

Answer 25

true

Question 26

what were the 2 models for prpsc

Answer 26

1: would be inherently more stable than PrPc,
but kinetically inaccessible
PrPsc would catalyze the rearrangement of a molecule
of PrPc to the more stable PrPsc conformation
Infection would depend upon the ability of PrPsc to bind to and
catalyze conversion of existing PrPc

2: CJD would result from a slow rate of
spontaneous conversion of PrPc to PrPsc
Familial syndromes would result from mutations
(a) increasing populations of unstable intermediates
or
(b) an increase in rate of spontaneous conversion
of PrPc to PrPsc

Question 27

How did people get kuru?

Answer 27

-fore people were canibalists
-men would get gppd parts
-women and kids would get bad parts
-when canibalism stopped so did kuru

Question 28

How did Mad cows disease got to cows

Answer 28

-in the uk in 1980s, the rendering ptocess for processing animal carcasses was changed
-this meant that dead animals infected with scrapie were fed to cows
-As a result scrapie crossed the species barrier into bovine

Question 29

True or false: kuru plaques look like alzeimers dementia

Answer 29

treu

Question 30

What are the symptoms opf mad cows

Answer 30

Cattle affected by Mad Cow
Disease experienced nervousness,
aggression, or other changes in
temperament; abnormal posture;
lack of coordination; difficulty in
rising; decreased milk production;
and/or loss of weight despite
continued appetite, followed by
death.

Question 31

True or false: mad cows disease never crossed human barriers

Answer 31

false it did
under the form of vCJD

Question 32

Distinct strains of prion can produce

Answer 32

-distinct and reproducible patters of incubation time
-distinct patterns of cns involvement
-distinct glycosylation and protein cleavage of prpsc

Question 33

vCJD

Answer 33

-vCJD is a disease distinct from sporadic CJD
-vCJD has a distinct pathology, a younger age of onset, and presents with psychiatric symptoms
-It is likely that vCJD is caused by a different prion strain that was less restricted by the species barrier than that of scrapie

Question 34

True or false: it is very easy for the scrapie prion to cross species barrier to primates

Answer 34

false

Question 35

True or false: prion transformation in the cow was initially stimulated by the scrapie prion

Answer 35

true