Lecture 13: Protein Misfolding and Disease II Flashcards

1
Q

How are scrapie (sheep), BSE (bovine), and CJD (humans) characterized?

A

transmissible spongioform encephalopathies (TSE) (prion diseases)

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2
Q

How can CJD be transmitted from humans to primates?

A

direct implantation of plaque

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3
Q

What are found in damaged areas of the brain after death by TSE’s?

A

amyloid plaques

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4
Q

What is the most definitive test for neurodegenerative diseases, such as TSE?

A

post mortem staining

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5
Q

although not the most definitive, what test can be used to detect neurodegenerative diseases?

A

PET scan

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6
Q

What did Prusiner do?

A

isolate protein which induces prion diseases
discover/isolate PrPc and PrPsc
no nucleic acid

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7
Q

What did electron micrographs reveal about TSE?

A

has islet amyloid polypeptide - organized fibrils

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8
Q

How is the infectivity of the TSE infective particle Not reduced? How is reduced?

A

NOT: conventional methods for sterilization (heat, irradiation)
Reduced: proteins denaturants (NaOH, SDS, guanidine hydrochloride)

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9
Q

How are the genetics of fatal familial insomnia and CJD similar?

A

common primary site mutation

either Met or Val at secondary site

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10
Q

How is PrP characterized? Where is it expressed?

A

glycoprotein

brain, other organs

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11
Q

There are two covalently identical forms of PrP. What does this mean?

A
exact same peptide
different conformations (fold differently)
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12
Q

How do PrPsc’s bind to one another? What is this called?

A

beta sheet

growth

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13
Q

When PrPc is converted to PrPsc, adnd several PrPsc molecules bind to one another, what is this called?

A

nucleation

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14
Q

List 4 characterizing features of PrPc

A
  1. non-pathogenic
  2. soluble
  3. protease sensitive
  4. 40% alpha helix, little beta sheet
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15
Q

List 4 characterizing features of PrPsc

A
  1. pathogenic
  2. insoluble
  3. protease insensitive
  4. 30% alpha helix, 45% beta sheet
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16
Q

There are a few models for amyloid fiber formation. In all of them, what motif is the building block for the amyloid fiber?

A

beta-helix

17
Q

What technique can be used to silence PrPc? What is the effect in mice?

A

siRNA silencing to create chimeric mice

survived scrapie infection significantly longer

18
Q

What therapeutic method for TSE is similar to PhiKan083 in p53?

A

stabilizing PrPc

pull equilibrium away from PrPsc

19
Q

What is the body’s immune response to PrPc and PrPsc?

A

no immune response

20
Q

What is the downfall to inducing an immune response to PrP?

A

Not specific to PrPsc - also targets Prpc

21
Q

What is the correct/healthy form of A-beta peptide?

A

A-beta 40 (cleaved)

22
Q

What is the incorrect form of A-beta peptide? What does it cause?

A

A-beta 42 (uncleaved)

amyloid plaques –> Alzheimer’s

23
Q

In addition to A-beta 42, what is commonly seen in neurofilbrilliary plaques?

A

aggregated tau

24
Q

What leads to aggregation of tau?

A

hyperphosphorylation of tau

25
Q

What single mutation protects against Alzheimer’s?

A

A673T

26
Q

What molecule cleaves A-beta40 –> A-beta42?

A

gamma secretase

27
Q

What three hypothesies explain the toxicity of amyloid fibrils in Alzheimer’s?

A

mature fibril is toxic
pre-fibril is toxic
amyloid fibrils are by-product of disease

28
Q

What is the structure of the A-beta amyloid fiber?

A

parallel, in-register beta sheets

29
Q

What have Alzheimer treatments done? What have they not done?

A

have decreased A-beta 42 levels

have not improved cognitive ability

30
Q

What happens in late diabetes? What molecule is associated with this?

A

beta cell crisis due to large scale apoptosis

islet amyloid polypeptide (IAPP)

31
Q

Increased _____ production leads to ______ levels of IAPP

A

insulin

increased

32
Q

What does IAPP bind? What are these structures known to do?

A

lipid bilayers

accelerate formation of amyloid fibrils

33
Q

When IAPP is viewed on a ____ wheel, a _____ face is apparent

A

helical

hydrophobic

34
Q

What is the structure of all amyloid fibers? What two interactions allow their formation?

A

beta sheets
side chain side chain interactions
peptide-peptide hydrogen bonds

35
Q

What type of modification blocks growth of amyloid fibers by blocking peptide-peptide h-bonds?

A

methylation

36
Q

What type of modification blocks growth of amyloid fibers by blocking side chain interactions?

A

introduce peptide with similar AA sequence

interactions will preferentially form with that peptide, and further growth will be stopped

37
Q

What are the two hypothesis for how soluble oligomers cause death?

A

pore hypothesis

receptor hypothesis

38
Q

what does the pore hypothesis explain?

A

curious finding that amyloid fibrils appear to have neutral or protective function in some diseases

39
Q

Which are more toxic: soluble oligomers of IAPP, or mature fibrils?

A

soluble oligomers