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MIMM 324 > 23. Prions > Flashcards

23. Prions Flashcards

1
Q

7 types of prion disease

A
  1. Kuru
  2. Creutzfeld-Jacob Disease (CJD)
  3. Variant Creutzfeld-Jacob Disease (VCJD)
  4. Gerstmann-Straussler-Scheinker Syndrome (GSS)
  5. Fatal Familial Insomnia (FFI)
  6. Mad-Cow Disease
  7. Bovine Spongiform Encephalopathy
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2
Q

what does “kuru” mean?

A

Shivering

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3
Q

6 steps of kuru disease progression

A
  1. Uncontrollable twitching
  2. Decreased muscular coordination/cerebellar ataxia
  3. Decreased ability to walk
  4. Dementia
  5. Muscle atrophy and paralysis
  6. Death
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4
Q

what is Kuru also called?

A

laughing illness

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5
Q

what does Kuru brain look like? (3 hallmarks)

A
  1. Lots of vacuolar spongiform degeneration of neurons
  2. Kuru plaques
  3. No inflammation
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6
Q

what type of material builds up in Kuru brain?

A

fibrous material

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7
Q

symptoms and pathology of kuru are IDENTICAL to:

A

Creuzfeldt-Jakob disease (CJD)

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8
Q

symptoms and pathology of kuru are SIMILAR to:

A
  1. Gerstmann-Straussler-Scheinker Syndrome (GSS)
  2. Fatal Familial Insomnia (FFI)
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9
Q

is kuru familial?

A

yes, families have high incidence of spongiform encephalopathy

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10
Q

what was the hypothesis for Kuru being caused by a gene? why?

A

sex-linked gene with age variation of incidence and gender

because mostly children and women were affected

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11
Q

is Kuru caused by a gene? why?

A

NO! Too high penetrance in population, a small community with such a gene would not survive

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12
Q

what happened when Kuru brain tissue was inoculated in various animals?

A

animals were NEGATIVE when reacted serum from affected patients against the tissue samples

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13
Q

what is the disease in sheep called?

A

Scrapie

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14
Q

5 symptoms of scrapie

A
  1. trembling
  2. ataxia
  3. weakness
  4. strange behaviour
  5. paralysis, death
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15
Q

histopathology of scrapie (3)

A
  1. spongiform encephalopathy without inflammation
  2. kuru plaques
  3. microfibrillar arrays
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16
Q

how was spongiform encephalopathy found to be transmissible?

A

2-5 years after the initial negative results were found, the animals who were initially inoculated were found to have spongiform encephalopathy

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17
Q

describe the only way to measure/detect kuru or scrapie infection initially

A

inoculate material into chimpanzee brains , then observe for 2-5 years

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18
Q

describe the new way to measure/detect kuru or scrapie infection

A

inoculate material into HAMSTER brains, then observe for 30-45 days –> much faster!!

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19
Q

what was found from inoculated brains?

A

analyzed tissue fractions on SDS-PAGE gels –> found a protein band that was not found in uninfected brains

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20
Q

what was weird about the infectious material inoculated in brains?

A

no viral agent or nucleic acid was found in infectious material

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21
Q

how did they know that the infectious material did not contain nucleic acid?

A

treatments that inactivated nucleic acids did not affect infectivity

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22
Q

what 4 treatments can be used to inactivate nucleic acids?

A
  1. UV light
  2. psoralens
  3. X-irradiation
  4. DNAse
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23
Q

what type of material was the infectious material?

A

protein

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24
Q

how did they know that the infectious material was protein?

A

treatments that inactivated proteins abolished the infectivity

25
Q

2 examples of treatments that inactivate proteins

A
  1. chemical denaturants (alkali, phenol, SDS)
  2. proteases
26
Q

3 components of the prion hypothesis

A
  1. infectious agent made entirely of protein
  2. no nucleic acid
  3. PRoteinacious agent of infectION
27
Q

what is the infectious agent called?

A

Scrapie Prion Protein (PrP)

28
Q

how did they find the gene for PrP? 5 steps

A
  1. Purified the protein band from SDS-PAGE
  2. N-terminal aa sequencing
  3. reverse translated the aa sequence into a nucleotide sequence
  4. used nucleotide sequence to make a probe
  5. used probe to find PrP gene
29
Q

what encodes for PrP protein?

A

host cell mammalian gene –> PrP gene

30
Q

what is the role of PrP gene?

A

function is unknown but we know it is constitutively expressed as a membrane protein

31
Q

what are 4 examples of tissues that PrP is expressed in

A
  1. neurons
  2. lymphocytes
  3. follicular DC
  4. intestinal epithelium
32
Q

what happens in PrP KO mice?

A

normal phenotype

33
Q

describe PrP in uninfected hosts

A

PrP migrates as a 33-35 kd protein (PrPc)

34
Q

describe PrP in infected hosts

A

an additional protein migrates as a 29-32 kd protein (PrPsc)

35
Q

what happens when PrPsc is treated with Proteinase K?

A

leaves a proteinase-resistant core PrP fragment

36
Q

what happens when PrPc is treated with Proteinase K?

A

PrPc is completely digested

37
Q

in general, how does PrPsc differ from PrPc?

A

post-translational modifications

38
Q

5 post-translational modifications in PrPsc

A
  1. glycosylation at 2 extra sites
  2. removal of N-terminal signal peptide sequence
  3. removal of C-terminal hydrophobic segment
  4. addition of C-terminal phosphatidylinositol glycolipid
  5. removal of various non-signal N-terminal aa residues
39
Q

2 consequences of PrPsc post-translational modifications

A
  1. 3D folding
  2. physical and biological properties
40
Q

is there a covalent difference between PrPc and PrPsc?

A

no

41
Q

difference in 3D structure of PrPc vs PrPsc

A

PrPc = 40% alpha helix, barely any beta sheet

PrPsc = 20% alpha helix, 50% beta sheet

42
Q

what is the consequence of the different 3D structures of PrPc and PrPsc?

A

PrPc is soluble
PrPsc is insoluble –> forms plaques in brain

43
Q

what is Prusiner’s statement of prion hypothesis?

A

A misfolded form of a protein can catalyze the refolding of other PrP molecules into the same misfolded conformation

44
Q

describe the nucleation-dependent polymerization model of PrPsc formation

A
  • normally, conversion between PrPc and PrPsc is reversible but PrPsc is less stable than PrPc
  • PrPsc aggregates promote conversion of PrPc by binding to and stabilizing the unfavoured PrPsc
  • therefore, requires an initial nucleation process by a seed that initiates aggregation
45
Q

what does the nucleation-dependent polymerization model not explain?

A

nucleation-dependent polymerization model does not explain familial disease

46
Q

what is the second model for PrPsc formation?

A
  • PrPsc would be more stable than PrPc but kinetically inaccessible
  • PrPsc would catalyze the rearrangement of PrPc to more stable PrPsc
  • infection would depend on ability of PrPsc to bind and catalyze conversion of PrPc
47
Q

what model does the second model of PrPsc resemble?

A

resembles the model of proteins where proteins are separated from true free energy minima by a large barrier

48
Q

in the second model, what would spontaneous cases of CJD result from?

A

CJD would result from a slow rate of spontaneous conversion of PrPc to PrPsc

49
Q

in the second model, what would familial syndromes result from? 2

A

mutations that:
1. increase populations of unstable intermediates
2. increase rate of spontaneous conversion of PrPc to PrPsc

50
Q

what was causing the spread of Kuru?

A

RITUAL CANNIBALISM

women and children ate brains –> therefore more spread of PrPsc

51
Q

what happened to Kuru once cannibalism stopped?

A

once cannibalism stopped, Kuru also stopped

52
Q

what caused the spread of bovine spongiform encephalopathy and mad cow disease?

A

in early 1980s, process for dealing with diseased animals changed so scrapie-infected material entered the animal feed food chains –> scrapie was found in bovines

53
Q

what happened to cattle affected by mad cow disease? (8 symptoms)

A
  1. nervousness
  2. aggression
  3. abnormal posture
  4. lack of coordination
  5. difficulty rising
  6. decreased milk production
  7. loss of weight despite appetite
  8. death
54
Q

which species did BSE cross into? what is this disease called?

A

crossed into humans to cause Creutzfeld-Jakob Disease

55
Q

distinct strains of prions can produce: (4)

A
  1. distinct and reproducible patterns of incubation time
  2. distinct patterns of CNS involvement
  3. distinct glycosylation and protein cleavage patterns of PrPsc
  4. distinct conformational misfolded structures of PrPsc
56
Q

is variant CJD the same as sporadic CJD?

A

no

57
Q

3 differences between vCJD and CJD

A
  1. vCJD has distinct pathology
  2. vCJD has younger age of onset
  3. vCJD has psychiatric symptoms
58
Q

difference btwn vCJD and scrapie

A

vCJD caused by diff prion strain that was less restricted by species barrier than scrapie

MIMM 324 (37 decks)

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