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BIOC3016 > Role of Protein Aggregation in NDD > Flashcards

Role of Protein Aggregation in NDD Flashcards

1
Q

What contributes to Protein Aggregation?

A 
-	Protein modification
o	Mutations of genes encoding the aggregating protein
o	Post-translational modifications
♣	Phosphorylation
♣	Nitration
♣	Etc.
o	Cellular stresses
♣	Oxidative damage
-	Inappropriate interactions
-	Increased protein levels
-	Abnormal protein levels
-	Abnormal protein degradation pathways
-	Altered trafficking
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2
Q

What are the disease causing mutations for PD?

A

SNCA - A30P, A53T, E46K, H50Q

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3
Q

What are the disease causing mutations for AD?

A

APP - K670N, A692G, I176V

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4
Q

What are the disease causing mutations for Prion disease?

A

PRNP - P120L, E200K

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5
Q

What are the disease causing mutations in HD?

A

HTT - PolQ >36

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6
Q

What are the disease causing mutations in FTD?

A

MAPT - P301L

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7
Q

What encourages aggregation?

A

Phosphorylation at residues serine, threonin and tyrosine, this makes the residue “bulkier” and its charge could potentially disrupt typically protein fold

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8
Q

What encourages Asyn aggregation?

A

Serine-129 phosphorylation

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9
Q

What encourages aggregation of tau?

A

Hyperphosphorylation of Tau fibrils

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10
Q

What is oxidative stress?

A

Oxidative stress is where there is an increase in species that can lead to oxidation, most commonly reactive oxygen species (ROS)

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11
Q

What are the pathways that can generate ROS?

A

o Mitochondrial Respiratory Chain (MRC)
♣ Main cellular site of superoxide formation, marked increased when MRC function disabled
o Activated phagocytic cells
♣ Neutrophils, macrophages, microglia, lead to release of O2, hydrogen peroxide and nitric oxide
o Auto-oxidation reactions
♣ Some biological molecules oxidise in the presence of O2 to form O2-
o Catalysed by transition metals:
♣ Fe2+ - Fe3+
♣ Cu+ - Cu2+
o Metabolic pathways
♣ Dopamine + O2 + 2H2O dihydrophenyl acetic acid + hydrogen peroxide + ammonia
o ER
♣ Cytochrome P540 system involved in detoxification, catalyses hydroxylation reactions involves superoxide generation

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12
Q

What are indicators of OX stress in PD?

A
  • Increased levels of free iron
  • Decreased levels of reduced glutathione
  • Decreased levels of polyunsaturated fats
  • Decreased Cu/Zn Super oxide dismutase activity
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13
Q

What are indicators of OX stress in AD?

A
  • Increased levels of DNA damage
  • Increased levels of Protein carbonyls and nitrotyrosine
  • Increased levels of lipid peroxidation
  • Increased iron and copper
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14
Q

What are the indicators of OX stress in HD?

A
  • Few indicators
  • Mitochondrial dsyfunction
  • Excitotoxicity which is thought to play a role in encouraging OX stress
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15
Q

What are the indicators of OX stress in ALS?

A
  • Excitoxicity
  • Neuroinflammation is thought to encourage the process
  • Mutations change the specificity of SOD1
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16
Q

What is the effect of OX stress on DNA?

A
  • OH forms an adduct with guanine
  • Can lead to dsBreaks
  • Can deaminate adenine - hypoxyanthinine
  • Changes the interactions with associated proteins, ultimately altering DNA replication signals, could silence or constituitively activate genes
17
Q

What is the effect on lipids?

A
  • OH can extract a Hydrogen from a hydrocarbon, ultimately leading to the formation of a carbonyl radical centre, ultiamtely two abstracted carbon radicals will bond to form a C2H6
  • This effects the lipid membrane constructs of the mito, membrane, organelles, lysosomes etc.
18
Q

How will aggregates encourage other proteins to misfold?

A

Through a process described as permissive templating, in which the misfolded protein acts as a template. Its highly exposed hydrophobic surface acts to attract protein structures of a folded proteins, encouraging segments to misfold.

19
Q

Whats the correlation between increased protein concentration and protein aggregation?

A

It is a positive correlation, it has been sugggested as the increase in protein synthesis is often coupled with an increase in degradation processes

20
Q

What do the Guiniers curve show

A

Using SAXS and SANS guinier curves were generated to show increased IgG concentration is coupled with increased aggregation.

21
Q

What is the evidence of misfolding occuring during translation?

A

There has been evidence of the upregualtion of HSP in Htt models

22
Q

What is the evidence of upregualtion of synthesis?

A

Triplifications in the SNCA gene

23
Q

What is evidence for decreased proteasomal effects in PD?

A

o Substantia nigra in PD patients have decreased proteasomal activity
o Inhibition of UPS in mice can mimic some PD features
o Lewy bodies are ubiquitinated
o Homozygous mutations of the E3 ligase Parkin are rare but important autosomal recessive cause of PD
o UCL-H1 mutation seen in a family with PD

24
Q

What is evidence for decreased proteasomal effects in AD?

A

o Striatum from HD patients has decreased proteasomal activity
o Htt aggregates are ubiquitinated

25
Q

Lysosomal function in ADD

A
  • Evidence in AD of increased lysosomes and autophagic vacuoles, implies inefficient degradation
26
Q

Lysosomal function in HD

A
  • Evicdence of increased macroautophagy a response to remove Htt aggregates
  • Treating cells with rapamycin which inhibits mTOR - (TORC1 activotor) suppresses TORC1 and initiates macroautophagy
27
Q

Lysosomal function in PD

A
  • Autophagosome build up
  • GBA mutations affects localisation of GCase to lysosome, effecting their function
  • Deffects in mitophagy
  • ATP132A mutations effect lysosomal function
  • LRRK2 mutations effect autophagy
28
Q

CMA defects in PD

A
  • Decreased Hsc70 and LAMP2A
  • Normal asyn is degraded by CMA but not when oxidised or nitrated
  • Phosphorylation at serine 129 might effect
  • CMA is inhibitied by A53T async
29
Q

What are oligomers?

A

Small associations of protein monomers, precursors to protofibrils

30
Q

What are protofibrils

A

Soluble short fibril of aggregated protein - aggregation intermediate

31
Q

Are oligomers or protofibrils toxic in AD?

A

AB42 is more prone to form oligomers and fibrils - more toxic - implicating both in apthogensis

32
Q

Are oligomers or protofibrils toxic in HD?

A

mutant Htt seen to form annular protofibrils which can form pores, disrupt membrane integrity and therefore cellular viabilitty.

33
Q

Are oligomers or protofibrils toxic in PD?

A

protofibrils seen in A53T mutants

  • -> alpha synuclein protofibrils are stabilised by interaction with dopamine - increases toxicity in cells
  • relevant to the type of neurones lost in PD
34
Q

What is AD’s relationship between disease progression and aggregate numbers?

A

Poor correlations

35
Q

What is PD’s relationship between disease progression and aggregate numbers?

A

None with LB

36
Q

What is HD’s relationship between disease progression and aggregate numbers?

A

More abundant aggregates in striatum were there is greater cell loss

37
Q

What links LB to survival in PD?

A
  • Cells that die have fewere inclusions

- Co-expression of synphilin 1 aggregates increased but cell death decreased

BIOC3016 (8 decks)

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