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Medical Biochemistry and Pathophysiology > Week 6B: Apoptosis, Fatty acid oxidation disorders, adrenoleukodystrophy > Flashcards

Week 6B: Apoptosis, Fatty acid oxidation disorders, adrenoleukodystrophy Flashcards

HC 33, 34, 35, 36

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1
Q

How is the regulation mechanism of apoptosis called?

A

Trigger-decision-execution

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2
Q

Apoptosis concept. And what happens to the debris made?

A

Proteolytic breakdown of nucleus, organelles and membrane
> Clearance debris by surrounding tissue

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3
Q

Pathology of failing apoptosis

A

Immune system defect
> Cancer

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4
Q

Which cells are prone to apoptosis

A

-Damaged cells
-Stressed cells
-Cells signalled by body signals

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5
Q

Process of apoptosis

A

-Initiation
-Shrinkage, form blebs, proteins for breakdown activated
-Enzymes break down nucleus and cell emits signals to attract macrophages
-Cell fragments with smaller pieces containing cell components and destroyed nucleus
-Macrophages recognize cell parts and removal

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6
Q

Which molecule is part of the electron-transport chain and apoptosis signalling?

A

Cytochrome c
> central sensor in apoptosis

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7
Q

Cytochrome c as sensor in apoptosis

A

-Mitochondria respond to cell stress
-Intermembrane space leak into cytosol, and there Cyt C becomes co-factor in apoptosis

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8
Q

Major players apoptosis (4)

A
  1. Caspases
  2. Death receptors: TNF/TNFR family
  3. Bcl-2 family: Bcl-2 like, Bax like, BH3-only
  4. Mitochondria as central sensor
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9
Q

Cyt C in cytosol is the cofactor for …

A

Apoptotic complex of Caspase9-Apaf1 > casp-9 generates more caspases and creates apoptosis

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10
Q

Caspase types

A

Initiator and executioner caspases

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11
Q

What kind of molecules are caspases?

A

Proteases which cleave proteins
> Highly specific functions
> Limited substrates
> Limited and directed process

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12
Q

Recognition sequence of caspases

A

They are cysteine proteases with unique specificity for cleavage after Asp residue

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13
Q

Caspases are made as zymogens, how are they activated?

A

Cleavage after internal Asp-residues
> can activate each other

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14
Q

Active caspase structure

A

Active heterodimer

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15
Q

Initiator caspases numbers and activation

A

Casp-8, Casp-9, Casp-10, Casp-2
> Long prodomain involved in activation

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16
Q

Executioner caspases numbers and activation

A

Casp-3, Casp-6, Casp-7
> Short prodomains, and cleave specific cellular proteins during apoptosis

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17
Q

In which processes are caspases involved?

A

-Some types in apoptosis initiator
-Some types in apoptosis effector
-Some types in cytokine maturation

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18
Q

Which caspase is the most active executioner caspase?

A

Casp-3

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19
Q

ICE

A

Interleukin converting enzyme, a cytokine maturation caspase

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20
Q

Death receptors (TNF-TNFR family) contain receptors present at this location:

A

Cell surface

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21
Q

Fas is a …

A

TNFR family member

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22
Q

Structure TNFR-family

A

Trimeric receptors
> trimeric ligands such as TNF, FasL and TRAIL

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23
Q

Result interaction ligand with TNFR-family (FasL binds Fas)

A

Trimerization of intracellular part: signalling
> intracellular interactions occur via specific domains and adapter proteins
> In Fas signalling: FADD (adapter) recruited which permits Casp-8 transactivation (protein-protein interactions)
> Casp-8 activation by induced proximity > apoptosis

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24
Q

Are all TNF-TNFR family members for cell death? How do they differ?

A

No, some for co-stimulation and survival
> Divergence in intracellular domains: bind different signalling molecules
> cysteine rich domains
> ligands are similar

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25
Q

Bcl-2 is a oncogene in …

A

Follicular lymphoma

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26
Q

Bcl-2 as oncogene

A

T(14:18) translocation juxtaposes IgVh enhancer (very active immunoglobin heavy chain enhancer in B cells) with Bcl-2
> oncogenic rearrangement
> Bcl-2 inhibits cell death as opposed to inducing proliferation

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27
Q

Role Bcl-2

A

Prevent mitochondrial Cyt C release when mitochondria are damaged
> Pro-survival state by expressing Bcl-2: inhibit apoptosis

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28
Q

Pro-apoptotic Bcl-2 family members

A

Bax-like: Bax, Bak

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29
Q

Anti apoptotic Bcl-2 family members

A

Bcl-2-like: Bcl-2, Bcl-xL, A1/Bfl-1

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30
Q

BH3-only members (pro-apoptotic)

A

Bid, Bim, Bad, Noxa, Puma etc

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31
Q

How is threshold for apoptosis determined

A

Balance between pro- and anti-apoptotic members of Bcl-2 family

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32
Q

What happens after activation Bax/Bak

A

Form oligomers and a pore in the membrane: leakage Cyt C

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33
Q

Homology Bcl-2 family

A

1-4 Bcl homology domains (BH1/2/3/4)

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34
Q

BH3-only subfamily activation types

A

-Transcriptionally induced: Puma, Noxa
-Present in dormant form: Bid, Bim, Bmf, Bad

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35
Q

BH3 peptides insert into …

A

Bcl-2-like or Bax-like proteins into hydrophobic groove
> selective interaction of Bcl-2 family members
> Some are promicuous like Bim and others more selective like Noxa
-Bim and Puma inhibit Bcl-2, Bcl-xL, Bcl-w and Mcl-2
-Bad inhibits Bcl-2/xL/w
-Noxa inhibits Mcl-1

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36
Q

Finetuning BH3 peptides by

A

expression certain members

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37
Q

Pro-apoptotic signalling

A

Activation BH3 peptides like Puma, Noxa, Bim and Bad by hypoxia, steroids, growth factor withdrawal, UV, Taxols or other drugs
> Inhibit Bcl-2-likes
Bax/Bak form complex to drill hole in mitochondrial membrane

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38
Q

Bcl-2-likes inhibit apoptosis by binding

A

Bax/Bak
> Bcl-2, Bcl-xL, Bcl-w, Mcl-1

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39
Q

Apoptosis pathways in lymphocytes

A

-Intrinsic pathway: Cyt C activates Casp-9
> Bcl-2 inhibits Cyt C release out of mitochondria
> DNA damage, cytostatic drugs, cytokine deprivation and metabolic stress induce Cyt-C release by activating BH3 pepides
> Activation ProCasp-9 bound by Apaf1: release and active.
-Death receptors/ extrinsic pathway: activation Casp-8 through FasL/Fas and recruitment FADD
> Casp-8 activates Casp-3 which causes apoptosis
> Flip inhibits activation Casp-8
-Cytotoxic T cells
> recognizing peptide on cell surfuce
> perforin release to make pore
> Granules with proteolytic enzymes: granzyme B into cell
> Bid to t-Bid by granzyme B
> t-Bid induces Bax?

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40
Q

CD95 is

A

Fas
And CD95L is FasL

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41
Q

What happens after Casp-3 activation?

A

-Cleavage ROCK1 > phoshatidyl serine exposure on outer leaflet after flip flop
-Cleavage of NDUFS1: subunit of respiratory Complex 1: shutdown
-CAD/ICAD cleavage: DNA fragmentation
-PARP cleavage: shutting down DNA repair
-Cleavage cytoskeletal proteins: actin, tubulin, fodrin and vimentin > membrane blebbing

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42
Q

Results Casp-3 activation globally

A

-Shutdown essential functions and repair mechanisms
-Disassembly of the cell into small fragments that are recognized and cleared by phagocytotic cells.

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43
Q

Necrosis

A

Passive cell death: damaged and blow up: swelling, membrane rupture and inflammatory response because contents are released

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44
Q

Necroptosis

A

Regulated form cell death
> Death receptor triggering and TNFa synthesis
> Necroptosome/RIPoptosome formation
> not details needed to learn

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45
Q

Name a form of cell death which involves iron

A

Ferroptosis

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46
Q

The neat form of cell death

A

Apoptosis
> cell fragmentation and clearance by macrophages
> immunologically silent > necroptosis is not silent

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47
Q

Necroptosis cascade

A

TNFa binds TNFR
> activation apoptosis through Casp-8
Or
phosphorylation and activation RIPK1/3 which activate MLKL by phosphorylation
> MLKL forms channel to release cytokines and inflammatory mediators and permeabilise the membrane

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48
Q

HC34: Explain the Ramos Burkitt lymphoma cell model

A

Model to detect apoptosis in the lab
> B cell line known for chromosomal translocations which changes apoptotic activity

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49
Q

How are Ramos Burkitt lymphoma cells triggered for apoptosis

A

aCD95: antibodies for Fas death receptor
aBCR: target B cell receptor
> trigger them
> detect properties using flow cytometry

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50
Q

Cell membrane change in apoptotic cells

A

Phosphatidyl serine on outer leaflet

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51
Q

Annexin V and PI for detecting apoptosis

A

-Annexin V binds phosphatidyl serine on outer leaflet and can be labeled by fluorescent label green (FITC)
-In late apoptotic cells: damage in PM, PI: propidium ionide goes in and binds DNA: once bound red fluorescence.
> Early apoptotic cells: Annexin V + and PI-
> Late apoptotic cells: double positive

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52
Q

Track phases of apoptosis with Annexin V and MitoTracker. Why is zVAD used in an extra analysis for apoptosis?

A

Shift to higher level Annexin V and then also lower MitoTracker.
> zVAD is a specific inhibitor of caspases

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53
Q

zVAD function in apoptosis detection

A

Specific inhibitor of caspases

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54
Q

aCD95 leads to early activation of caspase …

A

casp-8

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55
Q

aBCR + zVAD reaction in Ramos Burkitt lymphoma cells

A

drop in MitoT but not Annexin V
> mitochondria still damaged, but caspases not activated.

56
Q

Detection apoptosis using Western Blot

A

-Western Blot cyt C release and casp-3 processing after aCD95 and aBCR with leukemic B cells
> many fragments casp-3: processed and activated
> antibodies on blot

57
Q

Mitochondria are not part of lysate in Western Blot apoptosis detection. Is casp-3 activation faster in aCD95 or aBCR treatment of the leukemic B cells?

A

In aCD95 treatment
> cleavage, multiple fragments

58
Q

Detecting by blocking casp-9 activity genetically. How?

A

Dominant negative mutant casp-9

59
Q

The apoptosome contains:

A

Apaf, Casp-9, cyt C (heptameric structure)

60
Q

In the activation of caspases, the cysteine active centre is changed to ..

A

alanine

61
Q

How are CD95 and BCR triggering changed by dominant negative mutant of casp-9?

A

Blocking of the apoptotic pathway and mitochondrial damage
> casp-9 also involved in BCR triggered apoptosis

62
Q

What are JeKo cells and how are they used in apoptosis detection?

A

T-cells directed malignant B cells (are killed)
> different necroptotic and apoptotic JeKo cells
> Necroptotic morphology is different to apoptotis
-apoptosis: condensed nucleus
-necroptosis: blown nucleus

63
Q

Most apoptotic cells have … DNA. Which assay is used to detect this?

A

Sub-G1 DNA: fragmented
> shown with PI assay (propidium iodide)

64
Q

Detect apoptosis with enzymatic assays: Fluorometric protease assay

A

-DEVD: aspartic acid: D, cleavage site for caspase (3 for example)
> Cleavage DEVD-pNA > release fluorescent pNA molecule (or other chosen fluorescent molecule)
-Fluorometric protease assay

65
Q

Clonogenic survival assay for long-term survival

A

-Grow slowly, colonies to look at
-Long-term survival cells affected, or not
-Growth potential limited when less colonies formed
> detect if there is long-term survival!

66
Q

Assays for cell death detection (not apoptosis specifically)

A

-Metabolism - ATP -mitochondrial function
-MTT assays and variations

67
Q

Druggable target apoptosis

A

Inhibitors of Bcl-2 > specific > kill cancer cells which overexpress Bcl-2

68
Q

How to target resisting cell death cells directly or indirectly

A

Direct: Triggering pro-apoptotic BH3-only mimetics
Indirect: Blocking pro-survival signals

69
Q

Blocking prosurvival signals in cancer: how do cancer cells rely on signals from environment? (for which functions)

A

-To drive proliferation
-To prevent apoptosis
-To maintain adhesion

70
Q

BH3-only mimetics

A

-Pharmacological compounds that act like BH3-only proteins, and bind to prosurvival Bcl-2 members
> very effective against cancers that rely on Bcl-2

71
Q

ABT-737 function

A

BH3 mimetic that inhibits Bcl-2 and Bcl-xL

72
Q

Problem ABT-737

A

-Too effective > patients get bleeding because platelets need Bcl-xL
- Dose limiting toxicity: also active against healthy cells

73
Q

BH3 mimetic anti cancer strategy sequence

A

-Give activators of Bax/Bak: the BH3-only peptides
> get bound by Bcl-2 likes
> BH3 mimetics bind Bcl-2 likes
> Activators like Bim and Puma can bind and activate Bax/Bak
> Cytochrome C release > activation intrinsic apoptosis through caspases

74
Q

ABT-199 function

A

-Target cells which depend on Bcl-2 survival like cancer cells
-Little toxicity
> But: selection towards other Bcl-2-likes

75
Q

Chronic lymphocytic leukemia (CLL) cells traffic and growth

A

-Between lymph nodes and blood
-Cannot grow in blood > cycle back (because vulnerable for apoptosis)
> massive cell death in peripheral blood compartment
-In lymph nodes: protected from apoptosis
> 10,000 fold reduction sensitivity for ABT-199 after CD40-CD40L signalling in LNs
> increased resistance to novel drugs like BH3 mimetics
> Cells are flexible in apoptotic balance

76
Q

CLL cells in LNs which are resistant to drug treatment are … to the drug

A

refractory

77
Q

Inhibit pro-survival signals through BCR pathway

A

-Activate BCR
> Activates Bruton’s tyrosine kinase (BTK) in signalling cascade
> drug against BTK (essential in oncogenic signalling) in B cell malignant cell

78
Q

PCI-32765 function as drug (ibrutinib)

A

Abrogate BCR controlled signalling and adhesion
> inhibit fibronectin signalling (immunoglobin driven adhesion to fibronectin is inhibited)

79
Q

Effect BTKi (inhibitor) like PCI-32765 (ibrutinib)

A

CLL Cells cannot cycle anymore: adhesion prevention > cells flow from LNs to blood
> cannot go back because of BTKi
> slowly perish in blood

80
Q

Which chemokine promotes BTK

A

CXCR4

81
Q

Effect active BTK

A

Promote integrins for adhesion in lymph node
> proliferation and survival

82
Q

CLL combination treatment

A

BTKi + ABT-199
> impared proliferation + survival and induced apoptosis by forcing cells in blood and blocking Bcl-2-likes

83
Q

How can drug resistance against a BTKi occur?

A

Mutation at the site where the BTKi binds

84
Q

HC35: Where does translation of genes from mtDNA occur

A

In ribosomes in the mitochondria

85
Q

Which important organs rely on beta oxidation to gain energy

A

Heart, liver, skeletal muscles, the brain

86
Q

Chain reactions beta-oxidation

A

-Oxidation by chain length specific acyl dehydrogenases
-Hydration
-Oxidation
-Thiolysis: cleave acetyl-CoA off

87
Q

VLCADD

A

Deficiency in VLCAD
> inborn error of metabolism

88
Q

VLCADD is among the …. deficiencies

A

FAO deficiencies (FOAD), FA oxidaion

89
Q

Types of FOADs in expression

A

Severe neonatal onset or milder later onset
> newborn screening programs important

90
Q

Common complications of FOADs

A

-Cardiomyopathies
-Rhabdomyolysis (breakdown skeletal muscle)
-Hypoglycemia
-Muscle weakness and pain
-Fatigue

91
Q

FAO flux assay in VLCADD

A

Long chain FA oxidation flux variable between patients and can be increased when culturing at 30 degrees celsius
> FAO flux depends on FAO deficiency type in patients genes

92
Q

Which step is defective in VLCADD?

A

Breakdown long-chain fatty acids in oxidation reaction in beta oxidation in mitochondria
> Mutation ACADVL gene

93
Q

Consequences VLCADD

A

-Energy shortage (ATP)
-Accumulation of acylcarnitines and acyl-CoAs

94
Q

Clinical features liver, heart and muscle in VLCADD

A

Liver; hypoglycemia
Heart: Cardiomyopathy and/or arrhythmia
Muscle: myopathy, muscle weakness, possible hypotonia

95
Q

How is myopathy measured in the blood

A

Levels of Creatine kinase > 250 U/L while reference is 70-170

96
Q

Why newborn screening programs for VLCADD?

A

Prevent early-life complications
> know the patients and use cells for research

97
Q

However: what can’t the newborn screening program do for VLCADD patients?

A

-Cannot prevent late-life complications
-No prediction about when they will get sick
> But can give advice for specific diet

98
Q

Neonatal VLCADD characteristics

A

-Hypotonia
-Hypoketotic hypoglycemia
-Liver failure
-Cardiomyopathy
-Lipid accumulation in organs

99
Q

Late onset VLCADD characteristics

A

-Dark urine
-Recurrent rhabdomyolysis (breakdown muscle) after prolonged exercise
-High creatine kinase in blood&raquo_space;170 U/L (rhabdomyolysis detected)

100
Q

Why is it not possible to accurately investigate VLCADD in animals?

A

It does not correlate well with human disease
> different metabolisms
> humans use more FAs for fuel

101
Q

Disease triggers of VLCADD

A

-Infections
-Fasting
-Fever
-Prolonged exercise
> use of beta-oxidation

102
Q

Dietary advice in VLCADD

A

Eat lots of glucose but restrict Long-chain FAs

103
Q

Alternative disease model for VLCADD

A

Human induced pluripotent stem cells: hiPSCs
> from skin fibroblast sample: make hiPSCs and let them differentiate to specific tissue type like cardiomyocytes

104
Q

Disease markers VLCADD in hiPSCs

A

-Accumulation acyl-CoA
-Accumulation acylcarnitines (FAO does not proceed for long chain FAs)
-Low ATP
-Increased [Ca2+] flux

105
Q

Why are cardiomyocytes the preferred disease model for VLCADD?

A

Measure membrane potential
> decreased action potential compared to control cell line

106
Q

VLCADD cardiomyocytes have an increased Ca2+ transient, what does this mean

A

Higher amplitude of Ca2+ flux

107
Q

Effect VLCADD patient when giving resveratrol (RSV)

A

Upregulate mitochondrial content and therefore its functions
> more energy made
> more efficient VLCAD, upregulated
> increased membrane potential like the control
» resue abnormal action potential in mild VLCADD CM (cardiomyocytes)

108
Q

Effect etomoxir (ETO) in VLCADD

A

Block the CPT-1 enzyme and therefore FAO
> Prevent acylcarnitine accumulation in patients
> not overloading the FAO system
> Rescue membrane potential in CM

109
Q

Substrate FA lengths VLCAD

A

C12-16

110
Q

Why is the immune response and its crosstalk with metabolism relevant for FOADs?

A

It is a disease trigger
> Immune processes cost a lot of energy: FAs needed

111
Q

Which cytokine response is impaired in VLCADD?

A

IL-6 response to LPS (in bacterial cell wall) of skin fibroblasts

112
Q

Is the IL-6 response always impaired in VLCADD?

A

No, only when triggered using LPS
> when triggered with Poly(I:C) (molecule from RNA virus) > IL-6 synthesis and release

113
Q

LPS pathway

A

LPS binds TLR4
> signalling pathway to activate transcription of IL-6

114
Q

Which components of the LPS to IL-6 pathway are downregulated in severe VLCADD?

A

TLR4 mRNA and JunB expression

115
Q

Newborn screening in VLCADD can …

A

be life-saving when early diagnosis

116
Q

HC36: Adrenoleukodystrophy is a … disease and therefore more … get it

A

X-linked, more males

117
Q

Adrenoleukodystrophy (ALD) characteristics in prevalence and affected organs

A

Rare disease: 1:15,000
> X-linked (ABCD1 gene)
> VLCFAs
> affects brain, spinal cord, adrenal cortex and testes

118
Q

How are VLCFAs made (very-long chain)

A

By elongation of LCFAs like palmitate

119
Q

VLCFA breakdown in the ..

A

peroxisomes

120
Q

Which transporter is defect in ALD and what is its function?

A

ABCD1, transport VLCFAs to peroxisome
> VLCFA accumulation

121
Q

ALD is a ….genic disease

A

monogenic

122
Q

Is the onset of ALD predictable? How many males are affected by adrenal insufficiency before age of 10 y?

A

No, males can develop adrenal insufficienct from six months age or later in life
> affects 50% male patients before 10 y

123
Q

What deficiency is developed in hormones in ALD because of adrenal deficiency (males >6 months)

A

Glucocorticoid deficiency: no cortisol
> Life threatening
> Insufficient immune system because deficient cortisol production: too slow response
> well treatable with hormone replacement

124
Q

Cerebral leukodystrophy

A

Water accumulation in (back of) brain (ALD in males > 3 y)
> 30% males <10y affected
> diagnosis based on neurological symptoms: too late for HSCT (bone marrow stem cell transplant), only possible before neurological symptoms.
> most severe type

125
Q

How is adrenal insufficiency a risk factor for cerebral leukodystrophy?

A

Blood barrier may be open

126
Q

Which ALD patients are affected by myeloneuropathy (spinal cord disease)

A

Males: >18 y
Females >40 y

127
Q

Treatment myeloneuropathy

A

No disease-modifying therapy, only supportive

128
Q

Rational for ALD newborn screening

A

Preventive treatment, for example the bone marrow transplant prior to the neurological symptoms
> follow up and monitoring

129
Q

Wilson and Jungner Criteria for Newborn Screening and effect for ALD NBS in Netherlands

A

-Early diagnosis must be directly beneficial to the neonate (treatment)
> only the case for males in ALD
> no treatment myeloneuropathy, but treatment for adrenal deficiency and leukodystrophy
> only male newborns in the newborn screening program

130
Q

Biomarker ALD in NBS (newborn screening)

A

C26”0-lysophosphatidylcholine (C26”0-lysoPC)
> heel prick of blood

131
Q

What was a challenge of the SCAN pilot study for sex specific NBS for ALD

A

> identify males using dry blood spots
do not identify other untreatable diseases: lower quality of life)

132
Q

X-counter in NBS

A

Identify males
> Measure for chromosomes 3, 4 and 7
> Gene on autosomal chromosome and X (but not Y) chromosome
> same expression level: XX
> If 2/3 chromosome comparisons show same level: XX > exclusion because female

133
Q

Dutch 4 Tier ALD-NBS algorithm

A

Stop testing after a negative result in one of sequential tiers
Tier 1: C26:0-lysoPC: cutoff at 0.32 uM for positive
Tier 2: X-counter: XX excluded
Tier 3: C26:0-lysoPC test with less false positives (cutoff 0.150 uM)
Tier 4: ABCD1 gene sequencing

134
Q

What happens with newborns classified as ALD patient after ALD-NBS?

A

Referral to pediatric neurologist

135
Q

Long-term follow up ALD diagnosis after NBS

A

MRI every 6 months until 12 y/o and then every year

Medical Biochemistry and Pathophysiology (16 decks)

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