Neurotrophic factors Flashcards
Trophic
Cell survival role. Diffusible molecules derived from target cells that mediate long-term dependence between neurons and cells they innervate. Creating connections.
Trophic
Cell survival role. Diffusible molecules derived from target cells that mediate long-term dependence between neurons and cells they innervate. Creating connections. Retrograde signalling.
Tropic
Diffusible molecules derived from target cells that guide or orient the migration of other cells or cell processes (axons) towards the target. Happens early in development.
What happens in development? What is the mechanism that optimising connectivity?
Cells find their correct position and then connections are made.
Function of neurotrophins.
Many more input neurons early in development, selective cell death to match amount of target neurons.
Why are neurotrophic factors important?
After synaptic contact is made, neurons become dependent on the presence of ‘trophic’ factors secrete from the target neuron which are necessary for their survival. Axons sent out to reach target and become dependent. Info goes back to cell body.
Why do some neurons degenerate?
Lack of succesful interaction with target. Mediated by limited amounts of neurotrophic factors secreted by target area. Competitive situation. 20-80% die by apoptosis.
The neurotrophic hypothesis
Survival of developing neurons depends on the supply of a neurotrophic factor that is synthesised in limiting amounts in their target field. Fine tuned system.
Mintalcini and Cohen NP in medicine
Discovery and characterisation of the role of NGF in peripheral nervous system.
What are the approaches to prove that NGF plays ‘the’ role?
Gain of function approach - Inject into neonatal rates = increase in sympathetic ganglia.
Loss of function approach - blocking antibodies postnatal rats = loss of sympathetic ganglia.
Both - Study of transgenic and knock out/in animals.
What are some of the neurotrophic factor families?
Neurotropins, TGF-b, Fibroblast, Haematopoietic cytokines, Platelet-derived, epidermal, Insulin-like.
What are the receptors for neurotophins ?
Trks isoforms in membrane proximal regions and p75.
They operate the complete opposite functions
Binding preferences of neurotrophins for trk receptors?
1:1 ratio. NGF -TrkA
BDNF - TrkB
MT4/5 - Trk B
Nt3 - TrkA,B and C.
What are the mechanisms of function of Trk receptors and neurotrophins?
After binding of neurotrophins, the Trk receptors are internalised (in vesicles along microtubules) from the axonal membrane and can be transported to the cell body, where they induce changes in gene expression leading to cell survival. Without the relay of the information from neurotrophins, the cell goes to default of cell death.
What experimental evidence is there that supports the retrograde signalling idea?
Adding neurotrophibs exclusively to distal axons supports survival.
Disruption of Trk endocytosis (stopping vesicles) and pharmocological disruption of dynein-dep microtubule transports (stopping movement of vesicles) leads to apoptosis.
What are the different possibilities of interaction between neurons classes and neurotrohphic factors?
1 - Modular concept - individual neurotrophic factors for each neuronal subtype.
2. Fuzzy strategy - A particular neurotrophic factor maintains more than one neuronal type. (This is the correct strategy for neurotrophins)
Whats is the relevance of NF’s in Huntingtons?
Mutated htt (gene huntingtin) has much larger glutamine expansion than normal protein. Expansion of CAG repreat (expression of glutamine) at beginning of protein. Autosomal dominant - even if unmutated is available in same cell, mutated form dominant. The retrograde signals are affected. The cells in the cortex need a constant supply of NF. If it is lacking then the cells within striatum start to die via apoptosis.
Whats is the relevance of NF’s in Huntingtons?
Mutated htt (gene huntingtin) has much larger glutamine expansion than normal protein. The retrograde signals are affected. The cells in the cortex need a constant supply of NF. If it is lacking then the cells within striatum start to die via apoptosis.
What happens to the retrograde transport of TrkB/BDNF in huntingtons?
Normal htt (huntingtin) is an adapter molecule which helps clutch the vesicles to the microtubule. When htt is mutated, this clutching does not work. Vesicle cannot go back to cell body - death.
Guidance molecules
Axons take up gradient of nerotrophins and growth cone turns towards supply.
Neurotrophins
Cell survival - LTP in synapses , promotion in dendrites and axon branching.
Pro-neurotrophins
Cell death - LTD in synapses, reduction in dendrites and axon branching suppression.
?
BDNF can control a lot of different signally pathways but there are other molecules that contribute. Efficiency of synapses it hypercontrolled.
