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Biomed Season Finale > Amyloid based diseases > Flashcards

Amyloid based diseases Flashcards

1
Q

define primary amyloidogenic diseases

A

deposition of amyloid throughout the body
mainly antibody light chains
causes organ dysfunction - kidneys, nervous system, heart and GI tract

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2
Q

define a secondary amyloidogenic disease

A

chronic infection/inflammatory disease such as rheumatoid arthritis and osteomyelitis
mostly amyloid A protein deposits

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3
Q

define familial amyloidogenic disease

A

found in small number of families - found in every ethnic group
transthyretin is most common

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4
Q

define other types of amyloidogenic diseases

A

Alzheimer’s disease is one of them

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5
Q

what is used to identify amyloid deposits

A

congo-red

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6
Q

how are amyloid deposits detected in-vivo

A

I-SAP scintigraphy

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7
Q

what is the composition of amyloidogenic deposits

A

fibres - one protein
proteoglycans
collagen
serum amyloid P component (SAP)

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8
Q

in amyloid deposits what are the proteoglycans that compose some of it

A

heparan sulphate
dermatan sulphate
glycosaminoglycans

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9
Q

what are the ways we can determine the structure of proteins

A

x-ray diffraction
solution-state nuclear magnetic resonance

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10
Q

are they typical ways we study proteins structure sufficient for studying amyloidogenic deposits

A

no

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11
Q

what are some of the alternative methods employed to study amyloid deposits

A

electron microscopy
atomic force microscopy
circular dichroism
fluorescence
fibre diffraction
solid-state NMR

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12
Q

what does electron microscopy of amyloidogenic deposits show us about its fibril morphology

A

long thin fibres
composed of multiple protofilaments
typically helical

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13
Q

what does electron microscopy of amyloidogenic deposits show us about the protofilaments composing the fibrils

A

varies in width depending on the proteins
repeats along length

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14
Q

what is the structure of an amyloid fibril and what is the evidence for it

A

it is a cross beta structure
evident from x-ray diffraction studies

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15
Q

what is the separation between amyloid strands

A

4.8 atoms

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16
Q

how are amyloid strands packed and what is the distance

A

sidechain packing between sheets
distance of 5-12 atoms

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17
Q

how is protein folding achieved to achieve its native state (lowest energy conformation)

A

systematic search take too long - its a directed process
slowly increases number of favorable interactions - seeking lowest energy conformation

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18
Q

what is the route to amyloid fibrils

A

multiple ‘minima’ energy states for a protein exist that may not be its native state
proteins become trapped in native state because the amyloid structure is too thermodynamically stable - too much energy required to break out of it due to maximising the hydrogen bonds

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19
Q

how does molecular crowding affect protein folding

A

reduce space in which a protein can fold:
reduces configurational entropy
increase in deltaG
increase rate of protein aggregation

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20
Q

how do you get a monomer protein to a fibril

A

1 - monomer
2 - nucleation event
3 - protofibril elongation
4 - fibril formation

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21
Q

what is beta-2 microglobulin

A

a structure present in MHC class I

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22
Q

what happens to beta-2 microglobulin during dialysis for renal failure

A

dissociates from MHC I
rise in serum levels
leads to deposition of amyloid fibrils in joints

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23
Q

what is DRA

A

dialysis related amyloidosis

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24
Q

what is the composition of the DRA deposits

A

fibres
proteoglycans
collagen
SAP

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25
Q

what are the fibres in DRA deposits

A

beta-2 microglobulin
truncated beta-2 microglobulin

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26
Q

what are the proteoglycans in DRA deposits

A

heparan sulphate
dermatan sulphate
glycosaminoglycan

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27
Q

what is the structure of soluble beta-2 microglobulin

A

7 stranded beta-sheet fold
2 sheets composed of A,B,E,D and C,F,G residues on each sheet
D strand is split

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28
Q

how can we study the structure of beta-2 m

A

solid-state NMR
cryo-EM (electron microscopy)

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29
Q

what is the difference between using solid-state NMR and cryo-EM

A

solid-state NMR:
- local structure
- high resolution
cryo-EM:
- global structure
- low resolution

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30
Q

how does beta-2m form amyloid deposits

A

deletion of 6 N-terminal residues creating truncated beta-2 m
allows it to spontaneously form fibrils
25% of in-vivo deposits contain truncated beta-2 m

31
Q

what is the 2 step process to beta-2 microglobulin folding

A

one fast
one slow - higher energy requirement for cis/trans isomerisation of proline

32
Q

how do you remove the slow step in beta-2 m folding

A

changing proline 32 to a glycine removes the slow step

33
Q

is a high concentration of beta-2 m concentration sufficient for fibril formation

A

no
other factors are required

34
Q

how does deletion of N6 terminal residues affect beta-2 microglobulin

A

converts it into an amyloidogenic competent state
(truncated beta-2m)

35
Q

how does copper effect fibril formation

A

Cu2+ increases rate of fibrilisation

36
Q

how is copper present in the beta-2 m structure

A

Cu2+ is ligated to histidine 31
Cu2+ acts as a Lewis acid - interacting with lone electron pairs of the nitrogen group in proline 32

37
Q

how does the actions of copper affect beta-2m

A

destabilises the amide bonds
permits cis <—-> trans conversions

38
Q

what does stabilisation of proline 32 in the trans configuration lead to

A

leads to disappearance of the beta-bulge in the D strand

39
Q

what is the function of the beta-bulge and how does its disappearance effect fibril formation

A

prevents fibril formation
disappearance allows the D-strand to form more H bonds
allows for dimer formation

40
Q

what are the two types of deposits in Alzheimer’s disease and where are they found

A

neuritic plaques
neurofibrillary tangles
medial temporal lobe/cortical areas

41
Q

what are the plaque deposits composed of

A

composed of:
amyloid-beta peptide
serum amyloid P component (SAP)

42
Q

what are the tangle deposits composed of

A

hyperphosphorylated Tau protein
SAP

43
Q

what are the features of tau protein

A

microtubule associated protein
role in tubulin assembly
in AD, tau becomes hyperphosphorylated

44
Q

what are the features of amyloid-beta peptide

A

several forms
beta-stand structure at C-terminal
N-terminal is unstructured when in solution

45
Q

what does fibre diffraction of A-beta reveal

A

classical beta-sheet structure:
4.7A meridional spacing
~10A equatorial spacing

46
Q

what is the purpose of residues 15-23 and 28-35 in A-beta

A

involved in the formation of stable secondary structure in the core of the A-beta

47
Q

where does A-beta come from

A

processing of amyloid protein precursor
processing - cleavage of either the gamma/beta peptide

48
Q

what occurs if the alpha peptide of amyloid protein precursor is cleaved

A

prohibits the formation of A-beta
is antagonistic to beta/gamma cleavage

49
Q

what is the alpha secretase generally involved in

A

signalling:
basal activity
PKC activated

50
Q

what is beta secretase generally involved in

A

type-1 membrane protein
essential for A-beta formation
activity increases with age

51
Q

features of familial Alzheimer’s disease

A

genetic bases upon APP (chromosome 21)
presenilin-1/2 (PSEN1/2) - more abundant
all only accounts for less than 0.1% of cases

52
Q

features of sporadic Alzheimer’s

A

apolipoprotein E (e4 allele)
contribution of other genes to the disease to probably minimal

53
Q

how is the lipid composition of Alzheimer’s patients changed

A

+ cholesterol
+ polyunsaturated lipids
+ sphingomyelin
+++ lipid oxidation products

54
Q

what is required for A-beta to be toxic

A

at a monomeric level it is non-toxic
larger assemblies of it are required for toxicity

55
Q

what is a theory proposed for the toxicity of A-beta

A

intermediates (smaller oligomers) that mediate toxicity, ADDL - Amyloid-beta derived diffusable ligands

56
Q

what does injection of small oligomers into the brain cause

A

selective loss of CA1 neurons
effect is rapid with long term potentiation - blocked within 1 hour

57
Q

how does A-beta effect the cell membrane and what can it cause

A

membrane permeabilisation
done via the pre-fibrillar oligomers
effect ionic homeostasis - potential cell death

58
Q

what is transthyretin amyloidosis

A

fibrils formed from wild type transthyretin

59
Q

what are the features of familial amyloid polyneuropathy (FAP)

A

most common form of hereditary amyloidosis
associated with mutation in the transthyretin gene (TRR)
plasma TRR is produced excessively in the liver

60
Q

what is the composition of transthyretin plaques

A

transthyretin
SAP
heparan sulphate
apolipoprotein E

61
Q

features of transthyretin

A

14kDa protein
transports thyroxine/assists in retinol transport

62
Q

what is the structure of transthyretin (TRR)

A

tetrameric in solution
2-4 stranded anti-parallel beta sheets
dimer held together by H-H/F-F bonds

63
Q

what happens if you lower the pH environment of TTR to 4.5

A

decrease in hydrogen/deuterium exchange
loose contact with the core
causes change in loop/helix formation between E and F strands

64
Q

what do areas with high H/D exchange correspond to and what does it suggest

A

corresponds to where mutations are found
suggests that mutations destabilise contact between BCEF sheet and the core

65
Q

what are the ways in which we can treat amyloidogenic diseases

A

prevent precursor forming
prevent nucleation
stop fibril formation
enhance bodies ability to remove deposits

66
Q

how can reducing cholesterol in the cell reduce A-beta formation

A

reduced cholesterol increases alpha-secretase activity
cholesterol depletion favour non-lipid raft environment - lowers the chance of beta/gamma secretase being cleaved

67
Q

what can be used as a treatment for AD and why

A

statins
reduction in cholesterol levels

68
Q

what is the structure of SAP

A

pentameric doughnut like complex around the fibril
each subunit composed of 204 amino acids
possesses a Ca2+ dependent binding site - recognises a structural motif in amyloid fibrils

69
Q

how does amyloidosis affect SAP

A

elevated levels of SAP
persists in amyloid deposits - only catabolised when it re-enters the blood stream - catabolised by hepatocytes

70
Q

what is the concept behind a SAP based treatment to amyloidosis

A

SAP essentially coats the amyloid deposits - prevents body from clearing them
reducing SAP levels should allow the body to clear deposits
SAP null mice failed to develop amyloidosis normally

71
Q

how can we reduce circulation SAP levels

A

CPHPC prevents binding of SAP to Amyloid-beta fibrils

72
Q

how does CPHPC interact with SAP

A

binds to the Ca2+ binding site - prevents fibril binding
induces dimerisation of the SAP pentamer

73
Q
A

Biomed Season Finale (11 decks)

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