Neurotrophic factors Flashcards
trophic functions
diffusible molecules derived from target cells that mediate long-term dependence between neurons and the cells they innervate (cell survival)
tropic functions
diffusible molecules derived from target cells that guide or orient the migration of other cells or cell processes (axons) towards targets (local)
types of neurotrophins
-NGF
-BDNF (brain derived neurotrophin factor)
-NT3/4
how are neurotrophins produced
proteolytic cleavage of proneurotrophins
what do proneurotrophins and mature neurotrophins bind to
low affinity receptor P75NTR
which high affinity Trk receptors do neurotrophins bind to
TrkA: NGF NT3
TrkB: NT3 BDNF NT4
TrkC: NT3
how are neurotrophins involved in signalling
neurotrophin dimers bring 2 RTK molecules close so their cytoplasmic TK cross phosphorylate (downstream signalling)
how do neurotrophins contribute to neuronal survival and differentiation
SOS/Ras/MAP3 Kinase activate gene transcription
how do neurotrophins inhibit apoptosis
Trk and Ras activate phosphatidylinositol 3 kinase (PI3K) and AKT inhibits apoptosis
what do neurotrophins regulate
dendritic morphologies
synapse development
synaptic plasticity
how does receptor binding induce cell survival
trk receptors are internalised from axonal membrane and transported to the cell body where changes in gene expression cause cell survival
what do neurons undergo
competition for neurotrophins
if not enough received - apoptosis
Trk receptor phosphorylation
tyrosine amino acids are phosphorylated
more active kinase domain phosphorylates responding signals
2 types of neurotrophin action
Fuzzy strategy (combinatorial effect) - correct
modular concepts
fuzzy strategy
a particular neurotrophic factor maintains more than one type of neuron
what is a modular concept
each neuron subtype has one individual neurotrophic factor
what is huntington’s disease
autosomal dominant neurodegenerative disorder caused by expansion of 15 CAG repeats coding for Gln in particular proteins
which amino acid is Gln
glutamine
what is huntingtin (htt)
multifunctional proteins
20 residues of glutamine
what produces BDNF
striatum
what does HD cause
decreased antero/retrograde BDNF transport
BDNF transport
anterograde transport of BDNF from cerebral cortex to striatum (BG)
kinesins vs dynesins (motor proteins)
kinesins - anterograde transport
dyneins - retrograde transport
what does BDNF transport require
BDNF adaptor
HAP-htt
HAP = htt associated proteins
wt htt protein
neuronal survival by enhancing vesicle transport of BDNF/Trk along microtubules
mutant htt
attenuated BDNF transport
how do neurons attract axons
secreting BDNF at a gradient
how is growth cone steering directed
local polymerisation
depolymerisation of underlying cytoskeleton
post-translational processing of neurotrophins
proneurotrophins (low affinity for p75) converted to neurotrophins (high affinity for Trk)
via caspases (type of protease)
pro-neurotrophins
-cell death
-LTD
-dendrite reduction
-axon branching supression
-activate p75NTR
neurotrophins
cell survival
LTP
promotes dendrites
promotes axon branching - tropic effect reorients axons
how is pre synaptic NT release increased
PLC pathway activated, increased Ca2+ conc
MAP phosphorylation of synapsin
Rab3 expressed
post synaptic TrkB signalling
phosphorylation of voltage gated Na+/K+ channels and AMPA/NMDA receptor
AMPA receptor insertion
activation of TRP channels (Ca2+)/Rho GTPases/phosphatases - reducing GABA-R surface
local and global protein synthesis
what is the neurotrophic hypothesis
survival of developing neurons depends on a supply of neurotrophic factor synthesis in limiting amounts in their target field
