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BB20028 > Neurotrophins > Flashcards

Neurotrophins Flashcards

1
Q

What are neurotrophins?

A

A family of trophic factors for neuronal survival that are secreted by target cells (neurons or innervated tissues).

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2
Q

What is the neurotrophic hypothesis?

A

The idea that neurons depend for survival on a supply of neurotrophic factors synthesized in limiting amounts in their target fields.

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3
Q

What are some of the stages in neurodevelopment?

A

Determination, proliferation, migration, axon elongation, synapse formation and synapse rearrangement.

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4
Q

What happens once cells are committed to a specific neuronal phenotype?

A

They migrate to their destination due to attractant versus repulsive factors and extend their axon to establish synaptic contacts.

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5
Q

What later stages do trophic interactions support?

A

Survival of a subset of neurons, formation and maintenance of appropriate connections, growth of axonal and dendritic branches to support the connections.

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6
Q

What is the first recognised and best studied neurotrophin?

A

Nerve Growth Factor.

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7
Q

What are the features of nerve growth factor?

A

It is the best characterised neurotrophic factor, and was first identified as an activity necessary for neuron survival and neurite outgrowth.

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8
Q

What is NGF essential for?

A

Survival, it determines population size.

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9
Q

What happens if NGF is injected into immature animals?

A

There is enlargement of sympathetic ganglia.

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10
Q

What is the action of NGF dependent on?

A

Concentration - a limiting concentration would cause neurons to compete for it, such that only a proportion would survive and the rest would die.

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11
Q

How much NGF is produced naturally?

A

Only enough to promote survival of the required amount of neurons - it therefore determines the size of a neuronal population.

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12
Q

What happens if there is no NGF?

A

There is poor neurite outgrowth and neurons die.

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13
Q

What happens in the presence of NGF?

A

Neurite outgrowth is prolific and neurons thrive, but do not proliferate as NGF is a survival factor.

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14
Q

Why do neurons not proliferate under NGF?

A

It is a survival factor not a proliferation factor.

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15
Q

What effect does NGF have on neurites?

A

It has a local action - neurites grow in the presence of NGF and contact with a neuronal body is not needed. Neurite regression occurs if NGF is removed.

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16
Q

What is the structure of nerve growth factor?

A

It is a polypeptide of 118 amino acids with a molecular weight of 13,250.

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17
Q

What is each monomer of NGF composed of?

A

4 anti-parallel beta strands is connected by 4 loops. The beta strands are stabilized by three disulfide bonds.

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18
Q

What is the structure of NGF described as?

A

Cysteine knot.

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19
Q

What receptor does NGF bind to?

A

A membrane receptor called TrkA - tyrosine receptor kinase.

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20
Q

What is the role of the NGF receptor?

A

It converts the external signal (NGF) into an intracellular response.

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21
Q

What is the structure of the NGF receptor?

A

Trk (tyrosine receptor kinase) has leucine-rich repeats, cystein repeat motifs and immunoglobulin-homology molecules extracellulary, and a tyrosine kinase domain intracellularly.

22
Q

What part of the receptor does NGF bind to?

A

The Ig2 - domain 5, and potentially domain 2.

23
Q

What does binding of NGF to its receptor cause?

A

It activates the intracellular tyrosine kinase domain and causes structural changes that activate the tyrosine kinase by autophosphorylation. One monomer of TrkA phosphorylates Tyr residues in the other chain.

24
Q

How are the processes that NGF is involved with mediated?

A

A binding to its two cell surface receptors - TrkA and p75. Some of the processes involved include cell differentiation and survival, growth cessation and apoptosis.

25
Q

What pathways can the Trk receptor activate?

A

PI3 kinase, Ras and PLC.

26
Q

What are the different pathways the Trk receptor activates involved in?

A

PI3 = cell survival, ras = neurite outgrowth and neuronal differentiation, PLC = activity-dependent plasticity.

27
Q

How does TrkA interact with multiple targets?

A

Via phosphotyrosine.

28
Q

How is ras activated in the ras/raf pathway?

A

The phosphotyrosine residues on TrkA are bound by SH2 domains in Shc protein. Shc is tyrosine phosphorylated and then bound by SH2 domains in the adaptor protein Grb2. Grb2 is bound to sos protein that links membrane bound Ras, and this binding promotes the exchange of GTP for GDP to activate Ras.

29
Q

What happens once Ras has been activated in the ras/raf pathway?

A

Activated ras recruits cytoplasmic Raf kinase. Bound raf is activated and phosphorylates serine residues on MEK, another kinase. The substrate for MEK is ERK - MEK phosphorylates this (a MAP kinase). Phosphorylated ERK can phosphorylate multiple cytoplasmic targets or migrate to the nucleus to influence transcription factors.

30
Q

What happens to NGF that is bound to TrkA?

A

It is taken up by neurons and transported to the cell body/nucleus.

31
Q

What does binding of NGF induce?

A

Clathrin-dependent endocytosis of TrkA. The endocytosed vesicles recruit adater proteins and signalling effecters such as PI3 kinase, MAP kinase and PLCy. This is referred to as the signalling endosome.

32
Q

What else does NGF bind to?

A

A second receptor, p75NTR.

33
Q

What is the second receptor that NGF can bind to important in?

A

(p75NTR) - plays a crucial role in balancing survival-versus-death decisions.

34
Q

What are the characteristics of p75NTR?

A

It is a single-pass transmembrane receptor of the tumor necrosis factor (TNF) receptor superfamily. It has a low affinity for binding processed NGF, but also binds the unprocessed form with higher affinity.

35
Q

What pathways is p75NTR coupled to?

A

RhoA, c-Jun and NFalphaB.

36
Q

What can p75NTR promote?

A

Growth cone collapse and neuronal death via apoptosis, as well as cell survival.

37
Q

How can p75NTR interact with TrkA?

A

It can cooperate to increase the affinity of TrkA for NGF.

38
Q

What will the outcome of NGF signalling depend on?

A

The concentration of NGF, what receptors are present, the intracellular signalling molecules expressed and in the vicinity of the receptors and the longer term changes from internalised and trafficked NGF-TrkA.

39
Q

What is BDNF?

A

Brain-derived neurotrophic factor - the second neurotrophin to be identified.

40
Q

What is BDNF, NT3 and NT4/5 important in?

A

Survival factors for CNS neurons.

41
Q

Does NGF have much function in the CNS?

A

No, but it does support a population of cholinergic neurons in the basal forebrain.

42
Q

What are the physical features of BDNF?

A

It is structurally homologous to NGF and is released as a precursor proBDNF that is processed to BDNF. r.

43
Q

How does proBDNF and BDNF differ?

A

BDNF binds to another Trk receptor (TrkB) whereas proBDNF interacts with the p75 receptor.

44
Q

What are some of the Trk receptors?

A

TrkA, TrkB and TrkC.

45
Q

How do the different Trk receptors differ?

A

TrkA is limited to sensory and sympathetic neurons and a few brain neurons, whereas TrkB and TrkC are more widely distributed.

46
Q

What is GDNF?

A

It is a member of another family of neurotrophic factors that includes Neurturin, Artemin and Persephin. It is a 40kDa dimer.

47
Q

What receptor does GDNF bind to?

A

GFRalpha1.

48
Q

What happens when GDNF binds to its receptor?

A

Dimerisation of RET receptor is induced. The activation of the kinase domains causes phosphorylation of tyrosine residues that causes activation of intracellular signalling pathways.

49
Q

What is GDNF important in?

A

The development and survival of various neuronal populations - dopamine neurons.

50
Q

How is GDNF relevant in Parkinson’s disease?

A

Dopamine neurons die in Parkinson’s and GDNF has been considered as therapy for the disease.

BB20028 (7 decks)

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