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Medical Biochemistry and Pathophysiology > Week 7B: Parkinson's Disease: Basics, Apoptosis, Vulnerability SNc > Flashcards

Week 7B: Parkinson's Disease: Basics, Apoptosis, Vulnerability SNc Flashcards

HC 40, 41, 42

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1
Q

HC40: Symptoms Parkinson’s Disease

A

Involuntary tremulous motion, lessened muscle power (muscles stiffen), in parts not in action
> Shaking when resting: resting tremor
> propensity to bend trunk forward
> Slowness in movement (bradykinesia)
> difficulty walking

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2
Q

TRAP in Parkinson’s

A

-Tremor
-Rigidity
-Akinesia (slow (bradykinesia), to no movement (akinesia)
-Postural instability

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3
Q

Lewy bodies

A

alpha-synuclein aggregates in the pigmented neurons of the substantia nigra (SN)

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4
Q

SN neurons contain the pigment…

A

melanin

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5
Q

Basal ganglia

A

Subcortical nuclei responsible for primary motor control

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6
Q

Stimuli for movement path in brain

A

Cortex > travels to putamen and globus palidus segments to the thalamus
- SNc plays effect in stimulating striatum

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7
Q

SNr and SNc

A

SNr: substantia nigra pars reticula
SNc: substantia nigra pars compacta

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8
Q

Cortico-striatal pathways of basal ganglia (only the names, pathway details in other flashcard)

A

-Direct pathway: stimulates voluntary movements
-Indirect pathway: inhibits voluntary movement

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9
Q

Direct pathway cortico-striatal of basal ganglia
Decision is made in the cortex
Excitatory pathway

A

Cortex: Glutamate (Glu) >+ Striatum
SNc: Dopamine (DA) >+ Striatum neurons with D1 receptor (Gs)
Striatum: GABA >- GPi (Globus palidus int.) & SNr
GPi, SNr: GABA >- Thalamus
Thalamus: Glu >+ Cortical (for movement)
» So, the GPi and SNr are inhibited so that Thalamus is active

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10
Q

Indirect excitatory pathway via SNc

A

Cortex: Glu >+ Striatum
SNc: DA >- Striatum neurons with D2 receptor (Gi)
Striatum: GABA >- GPe (Globus palidus ext.)
GPe: GABA >- STN (subthalamic nucleus)
STN: Glu >+ GPi, SNr
GPi, SNr: GABA >- Thalamus
Thalamus: Glu >+ cortical (movement)
» So, the striatum inhibits the GPe which promotes inhibition of Thalamus via STN and GPi and SNr. > excitatory by blocking inhibition

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11
Q

SNc contain … neurons

A

Dopaminergic neruons

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12
Q

Defect which neurons in Parkinson’s disease (PD)?

A

Dopamine neurons in SNc

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13
Q

What kind of receptor is the DA receptor?

A

Trimeric G protein coupled receptor

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14
Q

Dopamine biosynthesis

A

Tyrosine is substrate
Tyrosine > L-DOPA (tyrosine hydroxylase)
L-DOPA > Dopamine (DOPA decarboxylase) (remove carboxyl group, from amino acid structure to amine only)
> monoamine neurotransmitter dopamine

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15
Q

Where does the dopamine synthesis for SNc occur?

A

In the cells themselves > in the cytosol

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16
Q

Dopamine biosynthesis pathway also used to make the hormones / neurotransmitter

A

Noradrenline and then adrenaline

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17
Q

Dopamine breakdown

A

Dopamine (DA) > DOPAL (dihydroxyphenylacetaldehyde) + NH3 (MAO-B)
(oxidative deamination)
DOPAL > DOPAX (dihydroxyphenyl acetic acid) (ALDH)

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18
Q

MAO-B characteristics

A

Monoamine oxidase B (MAO-B)
> Flavoprotein that catalyzes oxidative deamination
> oxidative: removal electrons, oxidation
> Flavoprotein is stuck with the electrons > cannot be donates to ETC (not in mitochondrium, just like VLCFA oxidation in peroxisomes)
> use molecular oxygen to accept electrons (high affinity for it)
> create hydrogen peroxide (addition two protons as well)

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19
Q

Loss dopamine neurons over time

A

SNc dopamine neurons are lost naturally over time due to aging
> but in PD: quicker loss DA neurons, quicker reaching threshold amount of neurons for symptoms
> amount of SNc neurons born with varies

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20
Q

What if DOPAL is not converted quickly after made?

A

It is an aldehyde: toxic > can create oxidative damage
> reactive

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21
Q

Treatment strategies PD (to prevent loss DA)

A

Stimulate synthesis or inhibit breakdown
> DA has longer half life if MAO-B inhibited

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22
Q

Prodromal stage symptoms of PD

A

-Loss of smell

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23
Q

Current most used treatment for PD

A

Levodopa (L-DOPA supplement)
> L-DOPA can be transported past blood brain barrier because it is an amino acid and amino acid transporter LAT-1 > DA is not! no transport!
> DA cannot diffuse through: charges > water shell attached
> transporter for amino acids but not for monoamines
> after L-DOPA reaches neurons, conversion to DA by DOPA decarboxylase

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24
Q

Levodopa treatment is in combination with … because …

A

Carbidopa, which inhibits DOPA decarboxylase in the blood
> it is no danger, cannot pass blood brain barrier
> prevents conversion L-DOPA to DA in blood, then it cannot pass the blood brain barrier

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25
Q

Genetics of familial PD: name the heritance of the protein markers and their function and presentation

A

-alpha-synuclein: Dominant heritance, early onset, involved in synaptic vesicle release
-LRRK2: Dominant, mid-late onset, signaling protein for synaptic transmission
-Parkin: recessive, juvenile PD, E3 ubiquitin ligase
-PINK1: recessive, juvenile PD, targets malfunctioning mitochondria
-DJ-1: recessive, early onset, cytoplasmic sensor of oxidative stress

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26
Q

Alpha-synuclein function

A

Protein involved in docking of vesicles with for example dopamine at the PM
> binds directly to synaptobrevin (VAMP) and stimulates assembly synaptic vesicle complex
> found in Lewy Bodies: forms fibrils when defect

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27
Q

LRRK2 function and in PD

A

Leucine-rich repeat kinase-2
> large kinase with many protein-protein binding domains
> involved in docking vesicles via activating the small GTPase Rab
> in dominant mutation: hyperactive: too much Rab phosphorylated, toxicity

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28
Q

PINK1 and Parkin are involved in the …
and the global path

A

PINK1/Parkin dependent mitophagy of damaged mitochondria
> Mitochondrion does not work: no ETC, no proton gradient, no transmembrane potential (depolarization): sensed by PINK1 (damaged mitochondrion recognized)
> Pink1 phosphorylates mitochondrion and binds Parkin > polyubiquitination mitochondrion
> autophagy and fusion with lysosome

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29
Q

What happens with Pink1 when normal mitochondrial transmembrane potential

A

Degraded via ubiquitination proteasome pathway
> Tail of Pink1 goes through mitochondrial membranes and in the matrix, the tail is cleaved by proteases there > released for degradation

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30
Q

Effect depolarization mitochondrial membrane potential of Pink1

A

Tail of Pink1 cannot go through into mitochondrial matrix anymore
> tail not cleaved, Pink1 not released
> dimerization Pink1 on mitochondria
> active Pink1 > auto-phosphorylation for fully active
> Phosphorylate mitochondrion proteins
> and phosphorylate and activate Parkin

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31
Q

Pathway Pink1/Parkin-dependent mitophagy

A

-Proton gradient lost, depolarization transmembrane potential
-Pink1 dimerization and activation by auto-phosphorylation
-Pink1 phosphorylates and activates Parkin
-Parkin (E3 ubiquitin ligase) ubiquitinates mitochondrial proteins (mitochondrion decorated by unusual phosphorylation and ubiquitination)
-Binding mitophagy receptors (OPTN) to ubiquitinated mitochondrial proteins
-Binding phagophore via LC3 (to OPTN)
-Elongation phagophore and engulfment of mitochondrion
-Fusion with lysosome
-Degradation mitochondrion

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32
Q

What if there is a defect in one of the proteins of the Pink1/Parkin-dependent mitophagy

A

Damaged mitochondria not recycled
> not enough energy
> SNc neurons use a lot of energy: sensitive to energy loss, die first due to loss ATP synthesis

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33
Q

Safe fusion mitophagosome and lysosome

A

Double membrane bilayers around mitochondrion in phagosome
> fuses with lysosomal bilayer (single membrane)
> while fusion, mitochondrion still in one bilayer membrane.

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34
Q

DJ-1 function and in PD

A

Sensor oxidative stress: redox-sensitive chaperone-like activity, active in oxidative stress
> specific cleft with Cys-106: putative binding site
> oxidized at Cys-106: sensor oxidative stress
> -SH (inactive, reduced thiol form) > -S-OH (transient) > -S=O-OH (protective active, reversible) > S=O=O-OH (protective active, irreversible)

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35
Q

Environmental causes PD: effect Rotenone

A

Rotenone: fish killer and insecticide
> inhibitor of ETC Complex 1
> Binds competitively to the multiple ubiquinone (Q) binding sites
> energy deprivation, SNc cell death

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36
Q

Carbon monooxide (CO) is toxic because…

A

It can block cytochrome c oxidase (ETC Complex 4)
> chance to generate ROS and energy deprivation

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37
Q

Trichloroethylene effect

A

Increases risk PD
> cleaning solvent
> correlation: possibly toxic

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38
Q

HC41: Is there a cure to prevent SNc cell loss

A

No, progressive loss over time

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39
Q

Side effect levodopa treatment

A

Serotonin neurons affected (whole brain gets the L-DOPA)
> L-DOPA taken up by serotonin neurons and converted to DA by AADC (DOPA decarboxylase?)
> Release 5-HT (serotonin) with DA in same vesicles
> Less 5-HT signalling in synaptic cleft
-Increasing dose needed after time: can get toxic

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40
Q

Rate limiting enzyme in PD

A

Tyrosine hydroxylase, in DA synthesis

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41
Q

Men get PD more ofter than women. But after the menopause, they may have risk factors, why then?

A

Estrogen has protective effects

42
Q

Search biomarkers PD, why

A

Lewy bodies only seen in postmortem histology
> early diagnosis and halting progressive decline of DA neurons could benefit patient

43
Q

Balance L-DOPA concentrations, what if too much and too little

A

Too much: dyskinesia
Too little: Akinesia/rigidity
Over time in PD progression: window of L-DOPA good concentration narrows

44
Q

L-DOPA in dopamine neuron terminal

A

Conversion to DA
> release upon activation
> re-uptake leftovers through DAT
> D2 binding on presynaptic membrane > Gi trimeric protein activated > inhibits DA (negative feedback)

45
Q

Prodromal symptom: REM-sleep behaviour disorder injury

A

Physical things done when in dreams: can cause injuries

46
Q

The risk factors (genetic) of PD, like alpha-synuclein, LRRK2, Pink1, Parkin and DJ-1 are expressed where?

A

In many neurons, but they do cause PD
> also expression in cortex: leads to behavioural changes in PD, dependent on the expression programs of the genes

47
Q

Length SNc neurons

A

Huge, 10 cm length in brain
> SN closer to midpart brain
> striatum more to the front, and the SN axons span across this distance.
> The SN neurons require immense amounts of energy because of this
> not enough ATP, first neurons to die

48
Q

Are there environmental protective factors for PD?

A

Yes, like coffee and Ca2+ channel blockers

49
Q

Observed in PD brains, which suggest a role of this cell death pathway in dopamine neurons

A

-Loss of cells
-Caspase 3 activity
-DNA cleavage
-Fragmented nucleus
> Apoptosis (intrinsic)

50
Q

Survival midbrain dopamine neurons depend on the Bcl2 factor … and the cell death during PD development is driven by …

A

Mcl1, driven by BH3-only factors (pro-apoptotic)

51
Q

Intrinsic apoptosis regulation

A

Bak/Bax form channels on mitochondria for cytochrome c release, activation Caspase-9 by bining complex with Apaf1 > activation Caspase-3 > cell death
-Bcl-2 likes inhibit Bak/Bax by binding them
-BH3-only factors, activated by cellular stress, bind and inhibit Bcl2-likes

52
Q

Name important Bcl-2 likes and BH3-only factors

A

Bcl2-likes: Bcl-2, Bcl-xL, Mcl-1
BH3-only: Bid, Bim , Puma, Bad

53
Q

Defect anti-apoptotic Bcl-2 like Bcl-2 factors leads to

A

Shift balance to pro-apoptotic Bcl-2 factors

54
Q

Bcl-2 modulators and growth factors can shift balance back to anti-apoptotic Bcl-2 factors. Is this a cure for PD?

A

No, delay cells death, but mutation and defect is still there, just longer symptom free.

55
Q

Apoptosome which can activate Casp-3 or 7 is made from?

A

Active Casp-9, activated when Cyt-C binds Procasp-9/Apaf1 complex

56
Q

Which Bcl-2 factor defect leads to SNc dopamine neuron death

A

Mcl1: highly dependent on it

57
Q

What is Pitx3 and what if KO

A

Homeodomain TF, activates a gene program
> mRNA Pitx3 specifically expressed in part which forms SNc dopaminergic neurons
> KO: absence SNc in adult

58
Q

Transient GFP assay

A

GFP replacement for one allele for a gene, for example Pitx3
> show expression in which cells > discovered that it was in SNc.

59
Q

If Mcl1 is functional inhibited, the CC3 and PI in cells are shown. CC3 is the cleaved caspase 3. Why is the PI marker also needed?

A

To see if the cell actually died (red DNA dye, dead cells, leaky membrane, PI goes through)

60
Q

Function Mcl1 under basal conditions

A

Bind Bax to keep it in inactive state

61
Q

Proximity ligation assay to measure Mcl1-Bax

A

Secondary antibodies coupled to oligonucleotides (PLA probes) > bind the proteins
> connector oligos ligate probes when in close proximity
> acts as primer for DNA polymerase > detection because oligos are coupled to fluorochromes
> spatial information on protein-protein interaction

62
Q

Where does Mcl1 bind to Bax?

A

In the cytosol

63
Q

Dopamine neurons are basally more vulnerable than non-dopaminergic cells, how is this seen in mice models?

A

Increased CC3 after Mcl1 functional inhibition
> Mcl1 functional inhibition also induces increased CC3 in SN of WT mice
> increased cell death in PD is not due to loss of one allele Pitx3 in GFP marking the cells

64
Q

Loss Pitx3 (entirely) leads to

A

Increase CC3 in dopamine neurons
> increased Noxa mRNA (pro-apoptotic BH3-only factor) > overexpression Noxa leads to induction caspase activation

65
Q

Which molecule can block Noxa

A

Bax inhibting peptide (BIP V5)

66
Q

Mcl1 leads to survival dopamine neurons because it …

A

inhibis Noxa-dependent apoptosis

67
Q

HC42: Which dopamine neurons are vulnerable in PD?

A

SNc, substantia nigra pars compacta

68
Q

Mesodiencephalic (midbrain) DA neurons originate from

A

Ventral midbrain (VZ: ventricular zone)

69
Q

Which enzyme marks DA neurons?

A

Tyrosine hydroxylase

70
Q

Radial glia cells

A

Progenitor cells which produce neurons in cerebral cortex
> cell bodies (somata) reside in VZ

71
Q

Development dopeminergic neurons in neural tube in WT signalling

A

Floorplate: DA neurons > Shh signalling strong there
> and little stripes into part baseplate as well

72
Q

Molecular distinction DA neurons: subgroups and relevance.

A

-Specific vulnerabilities may reside in molecular differences between SNc and VTA
> SNc, substantia nigra pars compacta
> VTA: ventral tegmental area

73
Q

Mutation Pitx3

A

Mutation in key TF in dopamine neuronal development leads to ablation SNc.
> in the basal plate

74
Q

Which DA neurons contain Pitx3

A

All of them

75
Q

Which important enzyme is activated by Pitx3

A

Aldh1a1 > Adh2 (aldehyde dehydrogenase)
> important in breakdown dopamine

76
Q

Remove Pitx3, only SNc die, not VTA, why?

A

VTA neurons in floor plate, only SNc neurons in basal plate affected

77
Q

Medial DA neurons (VTA) show … Adh2 expression and lateral neurons (SNc) show ..

A

VTA show restricted gene expression, Adh2 expression in SNc
> Ahd2 only expressed in subset of mdFA neurons
> Pitx3 regulates endogenous Ahd2 gene
> Ahd2 downregulated in Pitx3 -/- mdDA neurons

78
Q

Pitx3 -/- in SNc

A

No Ahd2
> Accumulation DA and DOPAL (aldehyde) because deficient breakdown
> reactive aldehyde
> only expressed in lateral position thus frontal area

79
Q

Retinoic acid production

A

-Retinol (Vitamin A) > retinaldehyde (retinol dehydrogenase)
-Retinaldehyde > (all-trans) retinoic acid (Retinal dehydrogenase
» Ahd2 required! aldehyde dehydrogenase can convert retinaldehyde to retinoic acid

80
Q

Why is all-trans retinoic acid needed

A

Conversion undifferentiated mdDA neurons to differentiated mdDA neurons

81
Q

Rescue SNc neurons when Pitx3 -/-

A

Supplement retinoic acid

82
Q

Complication not enough retinoic acid

A

Spinal cord problems

83
Q

SNc neurons need retinoic acid signalling to remain, what about VTA neurons

A

They do not require it that much

84
Q

RA signalling in SNc neurons: RA dependent pathway

A

Pitx3 binds Nurr1
> complex upregulates Ahd2
> Retinaldehyde > RA (Adh2 catalysis)
> RA > RAR-beta
> Expression D2R (D2 receptor) and Th (tyrosine hydroxylase) by RAR-beta/RXR-beta complex (neclear receptor)

85
Q

Pitx3 RA independent pathway

A

Pitx3/Nurr1
-Rostral mdDA
> Ahd2, Vmat2 (monoamine neurotransmitter transporter, like DA) , Dat (DAT, transporter re uptake), Th (tyrosine hydroxylase),
> inactivation Cck
Caudal mdDA
> Vmat2, Dat

86
Q

Cross-inhibiting function Pitx3/Nurr1

A

Meet in the middle
> rostrolateral mdDA neuron: Adh2 subset: RA signalling, inactivation Cck and En1 by Pitx3
> causal mdDA neuron: Cck subset. No expression Ahd2 and RA signalling, activation Cck by En1. > no cross-inhibition
» specific molecular coding differences lead to vulnerability of differetn mDA subgroups

87
Q

How many subgroups DA neurons

A

At least 12-14 > complex TF interplay

88
Q

Genetic variance in … influences pesticide toxicity towards PD (like paraquat, not rotenone) > toxicity depend on transport by …

A

DAT

89
Q

Turnover DA in the VTA is very …

A

Low
> less dependent on Adh2

90
Q

Character SNc compared to VTA

A

Very high arborization > many branches made
> more energy needed to maintain this
> higher bioenenergetic: more DA made, transported and secreted: energy demanding
> small error in energy metabolism leads to big problem

91
Q

Basal oxygen consumption SNc compared to VTA

A

Higher

92
Q

ROS production SNc and VTA

A

More in SNc
> quicker problems when something is wrong

93
Q

SNc have … axon length and amount of processes than VTA

A

Higher

94
Q

Mitochondrion density SNc vs VTA

A

Higher is SNc, matching its higher ATP needs and content

95
Q

Rotenone / paraquat induce blockade of …

A

Electron transport chain
> error in energy metabolism, SNc vulnerable
> higher survival VTA than SNc when giving those two.

96
Q

Which important transporter, which is blocked by paraquat, is high expressed in SNc

A

DAT

97
Q

SNc + Rotenone + Paraquat

A

SNc: energy dependent and dependent on DAT
> rotenone blocks Complex 1 and paraquat blocks DAT
> cell death

98
Q

Reducing axon arborisation in SNc

A

Sema7a treatment reduces axonal outgrowth
> reduces overall metabolic activity in SNc neurons
> increases resilience of SNc neurons to energy metabolism error
> reduces OCR (oxygen consumption rate)
> the treatment has no significant effect in VTA neurons

99
Q

The higher load of DA in SNc neurons induces…

A

Higher risk of toxic effects through aldehydes

100
Q

Which molecular distinctions induce specific vulnerability of SNc

A

-Differential DAT expression (higher load DA)
-Differential RA dependence
-Axon arborisation is higher

Medical Biochemistry and Pathophysiology (16 decks)

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