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A8 - Degeneration, Regeneration and Repair > ND disease - protein misfolding > Flashcards

ND disease - protein misfolding Flashcards

1
Q

Seminal Experiment

A

Anfisen- seminal experiments using ribonuclease A as model. Used 2- mercaptoethanol and urea to denature the protein, showed spontaenous refolding when conditions removed.

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2
Q

Reasons why we can’t rely on spontaenous formation (4)

A

1) Some proteins too big - levinthal’s paradox
2) Crowded intracellular environment -
3) folding is diffusional search on a free energy surface and molecules must cross energy barriers to fold correctly
4) some proteins are metastable - devoid of ordered 3D structure.

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3
Q

3 main mechanisms for proteostasis

A

Molecular chaperones
Ubiquitin-proteasome system
Macroautophagy

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4
Q

Molecular chaperone example

A

HSp70- associates with short peptide sequences rich in hydrophobic and basic AA, co-chaperone Hsp40 provides substrate specificity. Can act synergistically with UPS.

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5
Q

Example Chaperonin

A

TriC/CCT larger, barrell shaped complex that encapsulates substrates providing protected folding environment.

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6
Q

Major risk factor for AD

A

ApoE4 variant of apolipoprotein. Jiang et al. add to cultured microglia and measure degradation of GFP tagged Abeta. Facilitatory role for ApoE in proteolytic clearance of soluble Abeta, effect enhanced by liver X receptors.

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7
Q

Clusterin

A

Found to sequester aggregation prone species in the ECS- GWAS studies by Lambert (2009) show strong genetic link with LOAD.

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8
Q

Kopito (2001)

A

investigate protein aggregation impairing proteostasis systems. HEK expressed reporter protein with degron-GFP construct. Transiently expressed mutant Huntingtin- produced near complete inhibition of system. + feedback explain sudden loss of neuronal function?

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9
Q

Why do ND diseases increase prevalence with age?

A

1) protein aggregation is stochastic - requiring years to initiate disease.
2) age = decrease in detoxification efficiency, aggregates build up
3) Cohen C. elegans, toxicity of Abeta mutant decreased when aging slowed by decreased IGF1 signalling. Suggestive of mechanistic link between aging and proteotoxicity.

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10
Q

Cohen (2006)

A

Work with C.Elegans shown that aggregation mediated Abeta1-42 toxicity was reduced when aging was slowed by decreased IGF1-like signalling, central to regulation of longevity in worms. Suggestive of a mechanistic link between the aging process and proteotoxicity

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11
Q

Cotman and Pike (1991)

A

In vitro demonstration that non-toxic abeta peptide could be converted to a toxic species after incubation for several days in buffer. SDS page analysis revealed species to have high molecular weight.

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12
Q

McClean (1999)

A

showed how soluble Abeta oligomeric species could be extracted using saline buffers from brain tissues of AD patients. Prescence of these species was more strongly correlated with disease symptoms than amyloid plaques.

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13
Q

Why can’t the toxic oligomer be isolated? 3

A
  • possibility of artificially inducing oligomerization or denaturation during extraction or measurement.
  • Generating oligomers in vitro challenged by dynamic conformation of these proteins in aqueous solutions.
  • Possibility that a mixture of various aggregates and oligomers that interact with membranes and proteins in numerous non-specific ways.
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14
Q

Olzscha (2011)

A

cellular model based on expression of artificial proteins designed to form beta sheet structures, self assembling into fibrils in vitro. As de novo, effects attributed to aggregating protein alone, not loss of function. Expression in human cells lead to aggregation and toxicity- quantitative proteonomic analysis showed aggregates interacted with and sequestered many existing and new proteins.

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15
Q

What is the normal prion protein and what does it convert to? How do they differ

A

PrPc to PrPsc. Latter more beta sheets, amyloid fibrils form.

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16
Q

What characterises prion diseases? 3

A
  • Vacuolation
  • Astrocytic gliosis
  • Spongifrom deposition
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17
Q

Name 3 prion diseases

A
  • Creutzfeld Jakob disease
  • Fatal familial insomnia
  • Gerstmann-Straussler-Schinker disease
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18
Q

Kordower (2008)

A

Case reports show how grafted embryonic neurons transplanted into PD patients displayed slow but significant development of aggregates containing alpha-synuclein.

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19
Q

Eisele (2010)

A

cerebral beta-amyloidosis can be seeded in the brain by homologous protein aggregates delivered to the peritoneal cavity in transgenic mice

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20
Q

Kopito (2010) theory

A

Theorised that classical spread of neuropathology seed in both PD and AD could be attributable to spread along axonal pathways of infectious protein.

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21
Q

Ghammaghami (2009)

A

Quinacrine shown to block Prpx to Prpsc conversion, but shown in transgenic mice to transiently reduce Prpsc before they recovered. Drug promoted selective survival of drug resistant prion conformations.

22
Q

Treatment for AD

A 
acetylcholinesterase inhibitor (donepezil)
NMDA antagonist (memantine) reduce excitotoxicity. Both together statistically significant but clinically marginal effectiveness
23
Q

Treatment for PD

A

L-DOPA

24
Q

Function of beta secretase

A

Cleaves APP to abeta formation

25
Q

Sheridan (2015)

A

many significant phase 2/3 trial failures showing that this approach does little to alter the condition’s prognosis. Challenge to amyloid hypothesis.

26
Q

beta secretase drug

A

Aducanumab- antibody targeting BS. Ongoing phase 3 trials reduces soluble and insoluble Ab in dose dependent manner, accompanied by slowing of clinical decline.

27
Q

How many of those formally diagnosed with AD show no signs at autopsy

A

10-20%

28
Q

Clark (2011)

A

Phase 3 study- Florbetapir-PET for imaging beta amyloid distribution. Dependent on utility as marker.

29
Q

Levinthals paradox

A

Finding the natively unfolded state of a large protein by random search through all possible conformations would take enormously long time

30
Q

Meyer-Luehmann (2006)

A

Intracerebral injection of dilute Abeta-containing extracts from AD patients induced cerebral beta amyloidosis and associated pathology in APP transgenic mice.

31
Q

Braak

A

Devised staging system for PD progression by assessing immunoreactivity to alpha-synuclein.

32
Q

Braak staging (5)

A
  1. DNV- AOS
  2. medulla
  3. pontine tegmentum
  4. midbrain + basal forebrain
  5. cerebral cortex
33
Q

Challenges to Braak

A
  1. Zaccai (2008) half of 76 brains show staging, 17% have upstream pathology
  2. Saha (2000) in vitro study showing cell death can precede LB formation
34
Q

Wood (1999)

A

In vitro analysis of alpha synuclein showing mutant protein can seed aggregation of WT protein.

35
Q

Desplats (2009)

A

mouse cortical neuronal stem cells incubated in media contain fluorescent labelled alpha-synuclein. Immunofluorescence analysis shows co-culturing of neuronal cells overexpressing protein can lead to inclusion.

36
Q

How is transmission achieved? 3

A
  1. free diffusion through extracellular space
  2. transported in secreted exosomes
  3. Movement through intracellular tunnels called nano-tubes
37
Q

Kamenetz (2003)

A

increased neuronal activity enhances Abeta production in hippocampal slices that overexpress APP. In turn, Abeta suppresses excitatory synaptic transmission dependent on NMDA-R activity

38
Q

Selkoe (2009)

A

Showed in hippocampal slices that small soluble Abeta from numerous sources enhances synaptic depression by altering glutamate uptake, as extracellular glutamate scavenger restored soluble Abeta enhanced LTD to normal levels.

39
Q

How can neuronal dysfunction lead to damage?

A

Network instability and synchrony, leading to epileptiform activity and damage.

40
Q

Jowaed (2010)

A

analysed DNA in tissue samples from SNpc, putamen and cortex of sporadic PD patients and controls. Methylated CpG sites upstream to SCNA varied with location and disease.

41
Q

Asuni (2013)

A

Different strains of mouse prions that target different brain regions activate different combinations of chaperones. Shown using western blots.

42
Q

Serial dysfunction model

A

Neurons adversely affected by recieving improper signalling from earlier affected and misfiring neurons in their network

43
Q

Falling dominoes model

A

Area primed by network dysfunction induced stress, then oligomers act as scaffolds to seed formation of neighbouring aggregated, whilst protein incorporated into aggregated remain in their original location.

44
Q

Name the aducanumab phase 3 trial

A

ENGAGE

45
Q

German (2016)

A

IG3 biomarker in blood of PD patients using combinatorial peptoid library approach
84% accurate for de novo PD
+ correlates with disease severity

46
Q

Saiki (2005)

A

Neurons with DA phenotype generated from monkey ESCs. Behavioural improvement seen in MPTP lesioned monkeys following intra-striatal transplantation.

47
Q

Kim (2006)

A

Human NSC line produces L-DOPA through double transduction with cDNA for human TH and GTP cyclohydrolase. Transplantation into rat model enhanced L-DOPA production in vivo and elicited functional recovery

48
Q

Hemming (2007)

A

Fibroblasts expressing b-amyloid degrading protease neprilysin reduce plaque burden in mice

49
Q

Boyden and Tsai (2016)

A
  • Reduced g oscillations before onset of plaque formation or cognitive decline in mouse model of AD
  • g oscillations induced in PV interneurons through optogenetic manipulation decrease AB
  • Induction of genes associated with microglial activation
  • Non-invasive light flickering regime diminished Ab load in visual cortex of mouse models.
50
Q

Auluck (2002)

A

Dopaminergic cell loss in D. melanogaster when alpha-synuclein expressed. Directed expression of Hsp70 prevented dopaminergic neuronal loss

A8 - Degeneration, Regeneration and Repair (4 decks)

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