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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
what are the fibres in DRA deposits
beta-2 microglobulin truncated beta-2 microglobulin
26
what are the proteoglycans in DRA deposits
heparan sulphate dermatan sulphate glycosaminoglycan
27
what is the structure of soluble beta-2 microglobulin
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
28
how can we study the structure of beta-2 m
solid-state NMR cryo-EM (electron microscopy)
29
what is the difference between using solid-state NMR and cryo-EM
solid-state NMR: - local structure - high resolution cryo-EM: - global structure - low resolution
30
how does beta-2m form amyloid deposits
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
what is the 2 step process to beta-2 microglobulin folding
one fast one slow - higher energy requirement for cis/trans isomerisation of proline
32
how do you remove the slow step in beta-2 m folding
changing proline 32 to a glycine removes the slow step
33
is a high concentration of beta-2 m concentration sufficient for fibril formation
no other factors are required
34
how does deletion of N6 terminal residues affect beta-2 microglobulin
converts it into an amyloidogenic competent state (truncated beta-2m)
35
how does copper effect fibril formation
Cu2+ increases rate of fibrilisation
36
how is copper present in the beta-2 m structure
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
how does the actions of copper affect beta-2m
destabilises the amide bonds permits cis <----> trans conversions
38
what does stabilisation of proline 32 in the trans configuration lead to
leads to disappearance of the beta-bulge in the D strand
39
what is the function of the beta-bulge and how does its disappearance effect fibril formation
prevents fibril formation disappearance allows the D-strand to form more H bonds allows for dimer formation
40
what are the two types of deposits in Alzheimer's disease and where are they found
neuritic plaques neurofibrillary tangles medial temporal lobe/cortical areas
41
what are the plaque deposits composed of
composed of: amyloid-beta peptide serum amyloid P component (SAP)
42
what are the tangle deposits composed of
hyperphosphorylated Tau protein SAP
43
what are the features of tau protein
microtubule associated protein role in tubulin assembly in AD, tau becomes hyperphosphorylated
44
what are the features of amyloid-beta peptide
several forms beta-stand structure at C-terminal N-terminal is unstructured when in solution
45
what does fibre diffraction of A-beta reveal
classical beta-sheet structure: 4.7A meridional spacing ~10A equatorial spacing
46
what is the purpose of residues 15-23 and 28-35 in A-beta
involved in the formation of stable secondary structure in the core of the A-beta
47
where does A-beta come from
processing of amyloid protein precursor processing - cleavage of either the gamma/beta peptide
48
what occurs if the alpha peptide of amyloid protein precursor is cleaved
prohibits the formation of A-beta is antagonistic to beta/gamma cleavage
49
what is the alpha secretase generally involved in
signalling: basal activity PKC activated
50
what is beta secretase generally involved in
type-1 membrane protein essential for A-beta formation activity increases with age
51
features of familial Alzheimer's disease
genetic bases upon APP (chromosome 21) presenilin-1/2 (PSEN1/2) - more abundant all only accounts for less than 0.1% of cases
52
features of sporadic Alzheimer's
apolipoprotein E (e4 allele) contribution of other genes to the disease to probably minimal
53
how is the lipid composition of Alzheimer's patients changed
+ cholesterol + polyunsaturated lipids + sphingomyelin +++ lipid oxidation products
54
what is required for A-beta to be toxic
at a monomeric level it is non-toxic larger assemblies of it are required for toxicity
55
what is a theory proposed for the toxicity of A-beta
intermediates (smaller oligomers) that mediate toxicity, ADDL - Amyloid-beta derived diffusable ligands
56
what does injection of small oligomers into the brain cause
selective loss of CA1 neurons effect is rapid with long term potentiation - blocked within 1 hour
57
how does A-beta effect the cell membrane and what can it cause
membrane permeabilisation done via the pre-fibrillar oligomers effect ionic homeostasis - potential cell death
58
what is transthyretin amyloidosis
fibrils formed from wild type transthyretin
59
what are the features of familial amyloid polyneuropathy (FAP)
most common form of hereditary amyloidosis associated with mutation in the transthyretin gene (TRR) plasma TRR is produced excessively in the liver
60
what is the composition of transthyretin plaques
transthyretin SAP heparan sulphate apolipoprotein E
61
features of transthyretin
14kDa protein transports thyroxine/assists in retinol transport
62
what is the structure of transthyretin (TRR)
tetrameric in solution 2-4 stranded anti-parallel beta sheets dimer held together by H-H/F-F bonds
63
what happens if you lower the pH environment of TTR to 4.5
decrease in hydrogen/deuterium exchange loose contact with the core causes change in loop/helix formation between E and F strands
64
what do areas with high H/D exchange correspond to and what does it suggest
corresponds to where mutations are found suggests that mutations destabilise contact between BCEF sheet and the core
65
what are the ways in which we can treat amyloidogenic diseases
prevent precursor forming prevent nucleation stop fibril formation enhance bodies ability to remove deposits
66
how can reducing cholesterol in the cell reduce A-beta formation
reduced cholesterol increases alpha-secretase activity cholesterol depletion favour non-lipid raft environment - lowers the chance of beta/gamma secretase being cleaved
67
what can be used as a treatment for AD and why
statins reduction in cholesterol levels
68
what is the structure of SAP
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
how does amyloidosis affect SAP
elevated levels of SAP persists in amyloid deposits - only catabolised when it re-enters the blood stream - catabolised by hepatocytes
70
what is the concept behind a SAP based treatment to amyloidosis
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
how can we reduce circulation SAP levels
CPHPC prevents binding of SAP to Amyloid-beta fibrils
72
how does CPHPC interact with SAP
binds to the Ca2+ binding site - prevents fibril binding induces dimerisation of the SAP pentamer
73

Biomed Season Finale (11 decks)

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