L17 and 18 - Neurotrophins Flashcards
What are Neurotrophic factors (NF)?
Proteins which promote growth, differentiation and survival in NS
T/F: NF are not very potent
F- extremely potent
Viktor Hamburger - what did he find?
Showed in chick embryos that removing a limb bud = sensory and motor neuron loss, transplanting a limb bud = increased motor survival
Initially Hamburger thought that the extra limb was recruiting undifferentiated neurons into motor neurons,
Rita Levi-Montalcini
Showed in rodent embryos that using anti-NGF antibodies could prevent development of symp NS and using purified NGF increases numbers of symp nerves.
Neurotrophic hypothesis
Growing axons compete for limiting amounts of target-derived trophic factors (these travel retrograde from axon to cell body) and axons that fail to receive sufficient trophic support die by apoptosis.
What do cultures prepared from embryonic neurons need to be supplemented with?
Specific NF which corresponds with requirement for NF in vivo (what we use for the dish is what is used in the animal)
There is only one exogenous stimuli that will increase levels of neural stem cells (more BDNF produced) in our brain
Exercise
Couples in early romantic relationship (0-6 months) have twice as much ___ in their blood
NGF
BDNF is produced in the brain but also produced in?
Muscle
NGF - Promotes? Related to?
Protein dimer with cysteine bridges that promotes survival of symp, sensory neurons and cholinergic neurons
Related to TGFBeta and PDGF
BDNF - Promotes? Related to?
Promotes survival or sensory, motor and dopaminergic neurons
Related in sequence to NGF
NT-3 - Cloned on basis of homology between? Promotes?
Cloned on basis of homology between NGF and BDNF promotes survival of type 1A proprioceptive sensory neurons and various central populations
!3 Sources of neurotrophins
Target-derived
- NGF in targets of symp neurons
- BDNF in muscle
Paracrine sources
-BDNF upregulated in Schwann cells after axonal lesion
Autocrine
-BDNF in DRG (dorsal root ganglion) neurons promote DRG neuronal survival
2 types of neurotrophin receptors
TRK family of receptor tyrosine kinases
p75
!p75 - binds to? homologous to? KO leads to?
- Binds all NTs with low affinity (Kd = 10^-9 M)
- Homologous to CD40 and TNF receptor
- Role in apoptosis (p75 knockout leads to loss of sympathetic and sensory neurons BUT increased basal forebrain cholinergic neurons due to UNREGULATED cell death)
!p75 signalling pathways under investigation are
ceramide
JNK (phosphrylates c-jun)
NFkB
p75 of trk family involved in myelination? What inhibits myelination?
BDNF + p75 promotes myelination
NT3 + Trk C inhibits myelination
CNTF - related to? promotes?
A monomeric 4-helix bundle cytokine related to interleukin 6 (IL-6), leukaemia inhibitory factor (LIF) and oncostatin M (OSM)
Promotes survival of motor, ciliary and symp neurons
How is the CNTF receptor different to the trk receptors?
Cytokine-like - No intrinsic tyrosine kinase domain but recruits intracellular tyrosine kinases (JAK/TYK) upon ligand binding by using
NOT in neuronal targets but in Schwann cells
NOT release but acts as a lesion factor - CNTF knockout produces slow neurodegen
!BDNF - what two types of loops does it have? What mimetic peptides have been derived out of the two different loops?
Loop 2 mimetics that are trkB ligands (loop 2 dimeric peptides act as trkB agonists and are potent)
Loop 4 mimetics which are p75 ligands )loop 4 monomers aka dPAKKR are p75 modulators with drug-like properties: stable, light, crosses cell membrane, promotes peri myelination in vitro and in vivo)
!The BDNF Loop 2 mimetic - is it a monomeric monocyclic (circular) or linear peptide? amide or cysteine linkage works better? bicyclic or tricyclic? Full or partial agonist? How is it flexible?
Circular, amide, tricyclic, partial agonist, flexible as if the loops face diff direction it becomes an antagonist
a) What does dPAKKR (loop 4 monomers - Lys-lys-Arg-Ala-dPro = linker) promote?
b) What does it work independently of?
c) Is it stable in plasma?
d) Can it cross cell membranes?
e) low or high molecular weight
a) Neuronal survival and peripheral myelination (better effect compared to BDNF) in vitro AND in vivo where linker and p75 motif are both important for it’s activity
b) trkB - which is strange as it is suppose to be a peptide made from BDNF and BDNF does bind to trkB, BOTH phosphorylate MAP kinase though
c) Yes - this is important because they we can use it as a drug
d) Yes- same reason as c
e) Low - same reason as c and d
Increased or decreased BDNF in schizophrenic brain?
Increased
Increased or decreased NGF in injury, inflammation and chronic pain?
Increased as NGF sensitizes pain receptor TRPV1 and causes mast cell activation and increased sub P release from nociceptive neurons
