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Repair And Regeneration > Week 8 Part 2 > Flashcards

Week 8 Part 2 Flashcards

1
Q

What is Retrograde signalling of cytokines to sensory neurons (A)

A

After injury, CNTF is released from Schwann cells, LIF synthesis is induced in Schwann cells
IL-6 synthesis is induced in neurons
IL-1 and tumour necrosis factor alpha released at site of injury

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2
Q

Retrograde signalling (B)

A

CNTF, LIF and IL-6 activate the gp130 receptor which recruits Janus kinases to phosphorylation STAT3. pSTAT3 dimerises and be imported into the nucleus

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3
Q

Retrograde signalling (C)

A

STAT3 dimers bind directly to specific sequences in DNA

Induce transcription of many genes related to inflammation and repair

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4
Q

What are other molecules released by Schwann cells?

A

Other cytokines
Growth factors
Enzymes
Chemokines

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5
Q

Other cytokines

A

IL-1alpha, IL-1beta, TNF alpha (tumour necrosis factor alpha)

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6
Q

Growth factors

A 
GDNF
NGF
BDNF
NT-3
TGF-beta
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7
Q

Enzymes

A

Metalloproteinase 9 (MMP9)

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8
Q

Chemokines

A

MCP-1
CCL2
CCL3

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9
Q

What 2 molecules are used for axon regeneration?

A

GAP-43

SPR1A

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10
Q

What does macrophages and Schwann cells produce?

A

Matrix metalloproteases that interrupt the blood-nerve barrier

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11
Q

What is released when the blood-nerve barrier is interrupted?

A

CGRP
Substance P
Bradykinin
Nitric oxide

  • induct hyperaemia and swelling - promote the invasion of further monocytes and T lymphocytes
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12
Q

What is the role of CCL2 and CCL3?

A

Attract and guide monocytes to the lesion site

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13
Q

What is the role of macrophages and mast cells?

A

Release prostaglandin and cytokines

IL-1B, IL-6, IL-18, TNF and LIF

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14
Q

What does blood vessels have?

A

MCP-1

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15
Q

What do cells at injury site release?

A

Variety of cytokines

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16
Q

What does IL-10 from macrophages inhibit?

A

Fibroblasts and Schwann cells

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17
Q

What happens after nerve injury?

A

Expression of thousand of genes changes

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18
Q

What are regeneration associated transcription factors?

A

STAT3, ATF3, cJun, CREB, SOX11, SMAD1, KLF7, C/EBPdelta, p53

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19
Q

What are terminal RAGS?

A 
GAP43
CAP23
Galanin 
PACAP
Rac1
Cdc42
Arginase I
CRMP2
GDNF
BDNF
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20
Q

What does ATP released after injury trigger?

A

Neural responses to an injury

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21
Q

What does ATP release cause?

A

Peripheral cells to release cytokines

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22
Q

What is Calpain?

A

An intercellular Ca2+ dependent cysteine protease

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23
Q

How do neuronal bodies sense injury?

A

Rapid phase

Slow phase

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24
Q

Rapid phase

A

Injury-induced discharge of axonal potential and ions

Goes back to cell body

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25
Q

Slow phase

A

Conveyed by molecular motors

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26
Q

What is negative injury signals?

A

Interruption of normal supply of retrogradely transported trophic factors of negative regulators of neuronal growth from target

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27
Q

What is positive injury signals?

A

Retrograde transport of activated proteins at injury site

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28
Q

What does calcium wave lead to?

A

Molecular changes in the neuronal soma

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29
Q

What does sudden calcium change result in?

A

Body detecting there’s an injury

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30
Q

What is one of the molecules involved with calcium waves?

A

Histone deacetylase 5 with protein kinase

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31
Q

What does epigenetic change result in?

A

Histone acetylation

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32
Q

What does nuclear export of Histone deacetylase via protein kinase enhance?

A

Histone acetylation

Priming the chromatin for subsequent transcription events

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33
Q

What is a big player in peripheral axon regeneration?

A

Neurgulin

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34
Q

What does Neuregulin do?

A

Bind to receptor ERBB2 which is on the Schwann cells

It is released in the axons

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35
Q

What does axons have ?

A

TRKA receptors

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36
Q

What molecules are early injury signals?

A 
IL-6 family 
Gp130 family 
Neuropoietic family
Interleukin-6, IL-11, IL-27
Ciliary neurotrophic factor (CNTF)
Leukaemia inhibitory factor (LIF) 
Cardiotrophin 1 (CT-1)
Neuropoietin 
Cardiotrophin-like cytokines (CLC)
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37
Q

What does Neuropoietic cytokines activate?

A

JAK-STAT and MAPK pathway

38
Q

What are signalling pathways of neuropoietic cytokines?

A

Jak
STAT3
SOCS

39
Q

Jak

A

Janus-family tyrosine kinases

40
Q

STAT3

A

Signal transducers and activators of transcription 3

41
Q

SOCS

A

Suppressor of cytokine signalling

42
Q

Where is CNTF highly expressed?

A

Schwann cells

Has no signal peptide - not secreted by conventional pathways

43
Q

What is experimental evidence of earl injury signal?

A
  1. Phosphorylation and nuclear translocation of STAT3 was maximally induced within 12h post lesion in motoneurons of facial nucleus of wild type mice - maintained for 3 days
  2. In CNTF-deficient mouse, activation of STAT3 signalling was delayed by 10-12h
  3. Application of CNTF to transects nerve restored STAT3 activation in CNTF- deficient animals
44
Q

Why is LIF important?

A

Increases the regeneration state of injured neurons

45
Q

What are other transcription factors involved in injury induced responses?

A

ATF3

46
Q

ATF3

A

Injury marker
Regeneration marker
Pain marker

47
Q

What does the gene GAP-43 show?

A

Undergo axon growth

48
Q

What gets travelled all the way up to the injury site because the gene is made in the cell body?

A

GAP-43 and CAP23

49
Q

What does two sequential injections of ATP significantly promote?

A

Sensory axon regeneration in spinal cord

50
Q

What are demyelination pathways?

A

JIP

Calpain

51
Q

What is JIP?

A

JNK-interacting protein of scaffold protein

Mediate JNK signaling by aggregating specific components of MAPK cafe to form functional JNK signaling module

52
Q

What is calpain?

A

Intracellular Ca2+ dependent cysteine protease

53
Q

What gene is involved in WLDs?

A

NMNAT1

54
Q

Where is NMNAT1 located?

A

Nuclei
Also expressed in axonal cytoplasm
Organelle: mitochondria

55
Q

What are factors controlling early Schwann cell development and myelination?

A 
NRG1
B1 integrity’s
Claw paw
Laminin 
P75 NTR
TGF beta 
BRN2
Krox20/ NAB 1/2
NRG1
OCT6
56
Q

What does different types of neuregulin carry?

A

Epidermal growth factor (EGF) domain

5 matured forms are soluble

57
Q

What is matured type III ?

A

Membrane bound protein

Interact with receptors in Schwann cells

58
Q

What is ErbB proteins?

A

Type 1 transmembrane receptor tyrosine kinase

59
Q

What does Neuregulin 1 (NRG1) stimulate?

A

ErbB to dimerize

60
Q

What does ERB2 have?

A

Active kinase domain

61
Q

ErbB3

A

Binds to NRG1 but has an impaired tyrosine kinase domain

62
Q

ErbB4

A

Homodimers can bind to NRG1 and become activated

63
Q

What does NRG-III tell Schwann cells?

A

Myelinate axons

64
Q

What does injury have?

A

Growth cone

For axons to grow back again it needs to have growth cone

65
Q

What does growth cones have?

A

Microtubules which go all the way back to the cell body
Have actin surrounding
Fingers Filopodia

66
Q

What does P domain contain?

A

Unipolar actin filament bundles embedded in a less polar actin network
Contains: lamellipodia and filopodia

67
Q

What is T domain?

A

Thin interface between P and C domain

68
Q

Where is C domain located?

A

Centre of growth cone nearest the axon

Composed of microtubules and contains numerous organelles and vesicles

69
Q

What does membrane rupture lead to?

A

Elevation of the free intra-axonal ca2+

70
Q

What are the process of axon growth?

A

Protrusion
Engorgement
Consolidation

71
Q

What is protrusion?

A

Rapid extension of filopodia and thIn lamellar protrusion

extension are primarily composed of bundled and mesh-like F-actin networks

72
Q

What is Engorgement?

A

Microtubules invade protrusion bringing membranous vesicles and organelles

73
Q

What is consolidation?

A

F-actin depolymerises in the neck of growth cone and membrane to shrink around the bundle of microtubules to form a cylindrical axon shaft

74
Q

What does calcium wave lead to?

A

Molecular changes in the neuronal soma

75
Q

What is calcium wave?

A

Sudden change in calcium that results in cell body detecting there’s injury

76
Q

What is one molecule that’s involved in calcium wave?

A

Histone deacetylase 5 with protein kinase Cm

77
Q

What does epigenetic change result in?

A

Histone acetylation

78
Q

What does nuclear export of Histone deacetylase 5 via protein kinase activation lead to?

A

Enhancing Histone acetylation

Pruning the chromatin for subsequent transcription events

79
Q

Molecular changes in the neuronal soma?

A

Calcium ion flux into the axons
Released from internal stores
Generate calcium waves
Spread to soma and trigger gene expression

80
Q

What happens when there is damage to the axons?

A

Schwann cell axon interaction

81
Q

What is a key player in peripheral axon regeneration?

A

Neuregulin

82
Q

What is the role of Neuregulin?

A

Bind to its receptor ERBB2 (on Schwann cells)

Released in axons when injured

83
Q

What does axons have?

A

TRKA receptors

84
Q

What molecules are early injury signals?

A 
IL-6 family 
Gp130 family 
Neuropoietic family 
IL-6, IL-11 and IL-27
Ciliary neurotrophic factor (CNTF)
Leukaemia inhibitory factor (LIF) 
Cardiotrophin 1 (CT-1)
Neuropoietin
Cardiotrophin-like cytokine (CLC)
85
Q

Signalling pathways of neuropoietic cytokines

A

Shown through IL-6 receptor
JAK: Janus-family tyrosine kinases
STAT3: signal transducers and activators of transcription 3
SOCS: suppressor of cytokine signalling

86
Q

What is another pathway for regeneration?

A

PI3 kinase AKT pathway

87
Q

What is CNTF?

A

Early injury signal
Highly expressed in adult Schwann cells
Has no signal peptide - not secreted by conventional pathways
Can be released instantly after Schwann cell damage

88
Q

What is experimental evidence for CNTF?

A
  1. Phosphorylation and nuclear translocation of STAT3 was maximally induces within 12h post lesion in motoneurons of facial nucleus of WT mice and maintained for at least 3 days
  2. In CNTF- deficient mouse, activation of STAT3 signalling was delayed by 10-12h
89
Q

What is CNTF neuroprotective for?

A

Motoneurons
Sensory neurons
Retinal ganglion neurons

90
Q

Where is LIF mRNA levels increased?

A

Both proximal and distal stumps soon after PNI

91
Q

What is LIF important for?

A

Increasing the regeneration state of injured neurons

92
Q

What is bi-directional relationship between axons and Schwann cells during neural repair?

A
  1. Axons are re-myelinated
  2. Schwann cell begin re-myelination
  3. Schwann cells ensheath the axons
  4. As Schwann cells re-contact axons they proliferate

Repair And Regeneration (16 decks)

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