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MMI 445 > Lecture 10- Prions 101 > Flashcards

Lecture 10- Prions 101 Flashcards

1
Q

What was the first known prion disease?

A

Scrape

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2
Q

White circle in the brain are called?

A

Spongiform change

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3
Q

Hans Gerhard Creutzfeldt and Alfons Maria Jakob coined what term?

A

Creutzfeldt Jakob Disease (CJD)

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4
Q

What did Daniel Carleton Gajdusek study in 1957?

A
  • Went to Africa to study Kuru disease
  • Found that the disease primarily affected women and children
  • Tried to treat it but nothing happened
  • William Hadlow suggested doing an experiment to see if it was transmissable because it looked like scrape
  • It was found to be transmissible
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5
Q

Griffith suggested it could be a stand alone protein as the infectious agent because?

A
  • Infectivity resist UV that degrades DNA/RNA
  • Infectivity resists decontamination methods that work against known microbes
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6
Q

Stan Prusiner coined what term?

A

A prion

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7
Q

What is a prion?

A

A small protinaceous infectious particle

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8
Q

What is so unique about prion disease?

A
  • They can develop spontaneously
  • They can be inherited
  • They can be acquired
  • Prions are only proteins
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9
Q

What are the normal prion proteins?

A
  • PrPsen
  • PrPc
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10
Q

What does sen in PrPsen mean?

A

Means sensitive to protease digestion

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11
Q

What happens if PrPsen is digested with protease K?

A

It eats up the whole thing

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12
Q

What does the c in PrPc denote?

A

Cellular because this is a protein that is normally found on cells and its normal confirmation

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13
Q

Describe some characteristics of PrPsen and PrPc

A
  • Sensitive to proteases
  • Soluble in detergents
  • In diverse tissue
  • Apparent cellular roles
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14
Q

What are some cellular roles of PrPsen and PrPc?

A
  • Adhesion
  • Neuritogenisis
  • Resistance to oxidative stress
  • Metal binding
  • NMDAr binding
  • Abeta oligomers
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15
Q

What does a normal PrP do?

A
  • Its a facilitator molecule to help other membrane molecules work better
  • Its protective in conditions of oxidative stress
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16
Q

What happens if you remove a prion?

A

They will develop normally and look normal. But the moment you expose them under stress, they get a storke and the stroke in much larger

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17
Q

What are the disease PrP?

A

PrPres, PrPsc, PrPCDJ, PrPBSE, PrPCWD

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18
Q

What is the difference between a normal and infectious prion protein?

A

Same exact sequence but can only digest the beginning

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19
Q

Describe some characteristics of PrPres

A
  • Resistant to proteases
  • Form insoluable aggregates that acumulates in the tissue
  • Nervous system, lymphoid tissue
  • Associated with infectivity
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20
Q

What is the main difference in PrPsen and PrPres

A

The conformational shape

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21
Q

What is the conformation of PrPc?

A
  • 3 alpha helices (47%)
  • 2 small anti-parallel beta strands (3%)
  • Proteinase K (PK) sensitive
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22
Q

What accounts for the difference in bands in PrPc?

A

Size of band is different because of glycosylation

23
Q

What is the conformation of PrPsc?

A
  • Loses alpha content
  • Increased beta sheets
  • Proteinase K resistant
24
Q

On a gel, do the bands dissapear with PK digestion for PrPsc?

A

No the bands do not dissapear

25
Q

Describe the prion life cycle

A

(Conversion)
* Once it starts its conversion, it converts the neighbour prion protein and the next one
(Spread)
* Like a dominos effect
* This is what leads to pathology
* Need conversion process for infectivity
* Damages the membrane enough it can no longer cope

26
Q

What does it do to your brain?

A
  • Spongiform change
  • Neuronal loss
  • Astrocytosis
  • Accumulation of PrPres (strain dependent)
27
Q

What is astrocytosis?

A

Astrocytes when they react to invaders, a number of different insults, they become reactve and thats called astrocytosis (pink looking cells)

28
Q

CJD is a ____ disease

A

Rare

29
Q

What are the three types of CJD?

A
  1. Sporadic sCJD (90%)
  2. Genetic familial CJD (10%)
  3. Acquired vCJD, Kuru, Iatrogenic (<1%)
30
Q

What is sporadic CJD?

A
  • Spontaneous
  • Misfolding a protein and your immune system isnt fast enough to correct it, then it becomes efficient on spreading and the disease is on its way
31
Q

What are some types of genetic CJD?

A
  • Familial CJD
  • GSS
  • FFI
32
Q

Why was Kuru an acquired disease?

A

Because they were practicing cannabalism and were eating the brains and got infected that way

33
Q

Sporadic CJD is ______

A

Always Fatal

34
Q

What are some signs of sporadic CJD?

A
  • Ataxia
  • Cortical visual symptoms
  • Progressive dementia
  • Myoclonus
  • Akenetic mutism
35
Q

What is ataxia?

A

Problem with coordination and balance

36
Q

What is myoclonus?

A

Fast twitching movement

37
Q

What is akinetic mutism?

A

No movement and no speech

38
Q

What is the average time to death after onset of symptoms for sCJD?

A

4 months

39
Q

What is a definite diagnosis method for sCJD?

A

Neuropathological confirmation (need to look at the brain or isolate prion from the brain)

40
Q

Where are the two types on a gel?

A
Middle band is predominant = type A Upper band is predominant = type B
41
Q

What characteristic do you use for typing?

A
  • Codon 129 status
  • Glycoform ratio
  • Pattern of PK digestion will define the types
  • Have different phenotypes
42
Q

What is the difference between a probable and a possible diagnosis?

A

Possible is just clinical signs with no tests. Probable is both clinical signs and tests

43
Q

For a diagnosis, you need to have two of what clinical signs?

A
  • Myoclonus
  • Visual disturbances or ataxia
  • Pyramidal or extrapyramidal features (parkinson like slowness and stiffness)
  • Akinetic mutism
44
Q

For a diagnosis, you need to have one of what tests?

A
  • EEG periodic discharges, 1-2 Hz
  • MRI restricted diffusion (white is abnormal)
  • Positive QuIC
45
Q

Describe the process of QuIC (Quaking Induced Conversion)

A
  • You take a normal prion protein shown in yellow and mix it with the patient sample, usually spinal fluid
  • In there, there are a few misfolded protein, so what happens when you put them together = you get converison
  • Get build up of beta sheet aggregates
  • Have one big aggregate
  • Then you break up into smaller peices by shaking it
  • You add more of the normal, mix and repeat
  • Get an amplification of a beta sheet signal
  • Do it in the presence of thioflavin T = fluorescence indicator
46
Q

QuIC is highly ____ and ____

A

Specific and sensitive

47
Q

What treatments are there for sporadic CJD?

A

Only symptomatic treatments

48
Q

What are some potential future targets for prevention of sporadic CJD?

A
  • Suppress PrPc
  • Block conversion
  • Improve clearance
49
Q

The presence of PrPsc does not equal ____ and it is ____ dependent

A
  • Infectivity
  • Dose
50
Q

How is Iatrogenic CJD transmitted?

A
  • Dura matter graft and growth hormones
  • Not transmitted sexually or vertically
51
Q

Why does size and shape matter?

A

Because of the species barrier

52
Q

What is a strain of prion disease?

A

Defined as prion isolates that consistently induce a specific disease phenotype, pathology and incubation period in a given host

53
Q

What causes there to be different strains of prion disease?

A

Conformational differences

54
Q

What is conformational drug resistance and strain selectivity?

A

Prevent conversion to one shape, prions will just adapt (if you wipe out strain A, then you let strain B rise)

MMI 445 (26 decks)

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