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Phase 2 5. People and Illness > Protein folding and neurodegenerative disease > Flashcards

Protein folding and neurodegenerative disease Flashcards

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1
Q

Which amino acid does transcription always start with?

A

methionine

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2
Q

Which post-transitional modification targets the protein for destruction?

A

Ubiquitination

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3
Q

Where do the following proteins get degraded: - long half-life - membrane proteins - extracellular proteins

A

lysosome

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4
Q

Where do the following proteins get degraded: - short half-life - key metabolic enzymes - defective proteins

A

proteosome

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5
Q

What is the primary structure of a protein

A

amino acid sequence

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6
Q

What is the secondary structure of a protein

A

local folding (e.g alpha helix or beta pleated sheet)

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7
Q

What is the tertiary structure of a protein?

A

long-range folding will have a single polypeptide chain “backbone” with one or more protein secondary structures, the protein domains E.g. beta plypeptide of heme

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8
Q

What is the quaternary structure of a protein

A

multimeric organisation Protein quaternary structure is the number and arrangement of multiple folded protein subunits in a multi-subunit complex - e.g. RBC

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9
Q

What is the supramolecular structure of a protein?

A

large scale assemblies

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10
Q

What contributes to proteostasis?

A
  • synthesis - folding - processing - assembly - trafficking - localisation - degradation
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11
Q

What can a disruption in proteostasis lead to?

A

many diseases e.g. alzeimers

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12
Q

What is the primary structure of an amino acid?

A
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13
Q

Which amino acods have positively charged R groups?

A

lysine, arginine, histidine

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14
Q

Which amino acids have negatively charged r groups

A

aspartate, glutamate

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15
Q

Which amino acids have nonpolar, aromatic r groups?

A

phenylalanine, tyrosine, tryptophan

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16
Q

Which amino acids have polar, uncharged r groups?

A

proline, asparagine, glutamine, serine, threonine, cysteine

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17
Q

Which amino acids have nonpolar, aliphatic r groups?

A

glycine, alanine, valine, leucine, methionine, isoleucine

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18
Q

What would a conservative mutation infer?

A

The amino acid change will still have similar properties of r group

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19
Q

How does the cellular environment effect protein folding?

A

environment is hisghly crowded

  • increased tendenc for proteins to aggregate
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20
Q

What are molecular chaperones?

A

any protein that interacts with, stabilises or helps another protein acquire its functionally active confirmation, without being present in its final structure

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21
Q

What do chaperones bind to?

A

selectively bind to short stretches of hydrophobic amino acids

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22
Q

What are the proteome-maintenance functions of chaperones?

A
  • de novo folding
  • refolding
  • oligomeric assembly
  • protein trafficking
  • proteolytic degradation
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23
Q

Describe how chaperones work (in stages)

A
  1. newly created polypeptide emerges ribosome - a chaperon molecule will immediately bind
  2. as more polypeptide is made, more chaperone molecules will bind
  3. The polypeptide will then exit the ribosome, covered with chaperone molecules
  4. They create a cove for a protein to make its confirmational shape and then will dissociate
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24
Q

How do chaperonins differ from chaperones?

A

They form a cylinder shape, that the polypeptide is inserted into.

Protects the polypeptide from the external environment aqnd allows it to fold into its final confirmation

25
Q

What proportion of proteins do not fold properly?

A

~30%

26
Q

How do cells correct misfolded proteins within the ER?

A
  1. newly synthesised protein gets glycosylated in the ER
  2. glucosidases (I & II) will cleave all but one sugar groups
  3. the chaperone is able to bind to the one sugar group and allows the protein to fold
  4. Glucosidase II will cleave the sugar group, causing the chaperone to dissociate
  5. Assessed for correct folding - if correct, the protein will leave the cell, if not the cell will attempt to refold the protein
27
Q

How does the cell know if a protein has been correctly folded?

A
  • glucosyltransferase detects stretches of hydrophobicity

If the enzyme thinks the protein is incorrectly folded, it will glycosylate the protein and the protein will go through the process again

28
Q

What is a proteosome?

A

Large multimeric copmplex that degrades proteins

hollow cylindrical structure with a cap on both ends

29
Q

How do proteosomes degrade proteins?

A
  • label the protein with polyubiquitination, process requires ubiquitina ligases and ATP
  • the polyubiquitin tag is recognised by the CAP
  • polyubiquitin removed and the protein is unfolded
  • protein threaded through proteasome
  • proteolysis
30
Q

Give examples of types of proteinopathies

A
  • amyloidosis
  • prionopathy
  • tauopathy
  • synucleopathy
31
Q

What is amyloidosis causitive of?

A
  • alzeimers disease
  • familial british dementia
  • familial danish dementia
32
Q

What is prionopathy causative of?

A

Creutzfeldt-Jakob disease

33
Q

List examples of neurodegenerative diseases that result from tauopathy

A
  • fronto-temporal lobar degeneration
  • alzherimer’s disease
  • progressive supranuclear palsy
  • corticobasal degeneration
  • tangle predominant dementia
  • guam parkinson dementia complex
  • argyrophilic grain disease
  • pick’s disease
34
Q

What is synucleopathy causative of?

A
  • parkisnon’s disease
  • lewy body disease
  • multiple system atrophy
35
Q

What is alzheimers disease?

A
  • Most common form of dementia
  • Progressive and fatal, affecting language, memory, and vision, as well as emotion and personality
36
Q

What are the two forms of alzheimers disease?

A
  • early onset familial AD
  • sporadic AD
37
Q

What genes are associated with early onset familial AD?

A

Amyloid Precursor Protein (APP)

Presenilin -1, -2 (proteosomes)

38
Q

What gene is associated with sporadic AD?

A

ApolipoproteinE e4 allele

39
Q

What abnormal structures can be found in patients with alzheimers disease?

A
  • amyloid plaques in the extracellular space
  • neurofibrillary tangles in the cytoplasm

(both composed of misfolded proteins)

40
Q

What is the amyloid precursor protein?

A
  • thought to be involved in synaptic plasticity and neuronal development
41
Q

Describe the processing APP goes through normally

A

usually cleaved above the transmembrane domain by alpha-secretases to create soluble sAPPalpha

42
Q

Describe the processing of APP in people with alzheimers?

A

In the case of formation of amyloid beta peptide, it is abnormally processed.

Beta-secretase also cleaves the protein above the transmembrane domain at a different site

Then gamma-secretase cleaves the protein within the tansmembrane domain, which results in the release of this amyloid beta peptride

43
Q

What is a significant component of gamma-secretase and why?

A

presenilins - (defects in presenilins 1 and 2 are associated with early onset familial AD)

44
Q

Describe the amyloid hypothesis

A

peptide changes its shape - loses its alpha helical structure and assumes beta pleated sheet structure

These begin to accumulate, oligomerise and form plaques

45
Q

Describe neurofibrillary tangles

A

main components of tangles are paired helical filaments (PHFs) (long fibrous proteins ‘braided’ together)

consist of the microtubule-associated protein Tau

46
Q

What is tau?

A

microtubule-associated protein (microtubules v. important for transport in neurons)

appears as flame-like on staining

When tau binds to a microtubule, it stabilises it - remains polymerised

If you wanted to change the length of microtubule = remove tau through phosphorylation

47
Q

Describe phosphorylation of tau in the pathological state

A

too much phosphorylated tau:

  • tau filament formation => neuronal fibrillary tangles
  • microtubule dysfunction
  • cell death
48
Q

What are the possible causes of tau phosphorylation?

A
  • kinases, such as Cdk5, GSK3beta are implicated
  • downregulation of phosphatases
  • mutations in the tau gene that mimics phosphorylation
  • covalent modifications of tau

etc.

49
Q

Describe the process of neurofibrillary tangles

A

detachment of tau from MTs; increased unbound tau => misfolded tau => pretangles => b-sheet-containing structures (PHFs) => neurofibrillary tangles

50
Q

Describe dementia with lewy bodies

A

Shares symptoms with Alzheimer’s and Parkinson’s diseases

Presence of cortical Lewy Bodies

alpha-synuclein aggregates

51
Q

What is synuclein?

A

The most abundant neuronal protein, but function is still unknown

52
Q

Describe the changes of synuclein in dementia with lewy bodies

A

misfolding of alpha-synuclein into b-pleated sheet structure of a-syn (dimers, trimers and oligomers) that further aggregate into higher-order insoluble structures (fibrils): the building blocks for Lewy bodies

53
Q

What are transmissible spongiform encephalopathies (TSEs)?

A

aka. prion disease/prionopathies

very rare but extremely progressive and fatal

  • loss of motor coordination and behavioural changes
  • can be inherited/ sporadic/ acquired
  • long incubation periods
  • characteristic spongiform changes associated with neuronal loss, and a failure to induce an inflammatory response
  • aetiological agent: prion
54
Q

What does prion disease look like histologically?

A

neuronal loss = ‘vacuolation’

within spongiform area is an amyloid plaque

55
Q

What are the similarities between CJD and AD?

A
  • both fatal neurodegenerative diseases
  • inherited and sporadic forms
  • amyloid deposits
  • increased b-sheet secondary structure
56
Q

What are the differences between CJD and AD?

A

unrelated proteins: APP (amyloid b peptide) PrPC (PrPSc)

PrPSc is infectious

57
Q

What is prion seeding?

A

Prions can self-aggregate and propagate

PrPsc can bind to PrPc and somehow make the PrPc change its shape to become PRPsc

58
Q
A

Phase 2 5. People and Illness (21 decks)

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