Axonal Regeneration Flashcards
Describe the mechanisms of the the CNS injury pathway
CNS injury -> membrane depolarisation -> Ca2+ influx -(kinases + signalling}-> different genes on and off
Macrophages recruited and astrocytes + microglia proliferate-> release of chrondoitin sulfate and proteoglycans (CSPG)-> glial scar formation
Myelinated fibre disrup -> (MAG, OMgp, Nogo) -> RhoA -> growth cone collapse
Describe the PNS injury pathway
NGF enters through the break in the membrane and is endocytosed -> retrogradely transported -> activates transcription factors for regenerative promoting genes
PNS signalling -> upregulates CREB and downregulates RhoA -> axonal regeneration
How astrocytes cause growth cone collapse
Astrocytes release CSPG -> PTP-sigma receptor/Nogo receptor -> RhoA ->…-> growth cone collapse
How oligodendrocytes cause growth cone collapse
Damaged oligodendrocytes -> myelin proteins exposed (Nogo, MAG, OMgp) -> RhoA ->…->growth cone collapse
Main molecular pathways and mechanisms underpinning regenerative failure?
Extrinsic Signals
- astrocytes (CSPG)
- oligodendrocytes (MAG, OMgp, Nogo)
- ephrins/semaphorins
Intrinsic Signals
- neurotrophin
- integrin receptor
- retinoic acid
- mTOR
How ephrin/semaphorin cause growth cone collapse
Ephrin/semaphorin -> RhoA -> … -> growth cone collapse
How Retinoic acid contributes to axonal growth patterns
Retinoic acid (binds to intranuclear RA receptor) -> promotes intrinsic growth and inhibits inhibitory pathways ]- it represses gene activation of Lingo-1 (Nogo complex co-receptor), resulting in a downregulation of pathways that would normally cause growth cone collapse
Intrinsic axonal growth signals for targeted therapies?
- neurotrophins
- integrin receptor
- retinoic acid
- mTOR
Neurotrophin MoA?
Trk receptor -> cAMP -> PKA -CREBphosph-> pro-regen genes
NOTE: IL-6 works via a similar pathway
Injury -> inflamm -> IL-6 -> Gp130-Jak dimer -> STAT 3 phosph -> pro-regen genes
NB: could try and promote Trk signalling OR increase IL-6 expression
Integrin receptor MoA?
Intracellular cascade (FAK) -> promotes axonal growth
NB: could try to overexpress integrin receptors
Comparing CNS in different parts and PNS regarding regenerative ability
PNS > CNS (dorsal columns) > CNS (corticospinal tract)
List some examples of how regenerative neuroscience is trying to promote axonal growth
Nogo antibodies, chrondoitinases, cAMP analogues/phosphdiesterase inhibitors, taxols, PTEN deletion, Sox11 overexpression, RhoA inhibitors, Nogo receptor knockout, epigenetic modification, histone deacetylase inhibitors (HDAC3)
Chrondoitinases mechanism?
Chrondoitinases: dissolves CSPG, axons grow past lesion inhibits glial scar]- administered by lentivirus
CAMP analogues/phosphodiesterase inhibitors mechanism?
cAMP analogues/phosphodiesterase inhibitors: stimulate growth cone remodelling (lack specificity)
Taxols mechanism?
Taxols: stabilises microtubules, prevents growth cone collapse, reduces glial cell motility and reduces glial scarring,
PTEN deletion mechanism?
PTEN deletion: PTEN inhibits mTOR, increased corticospinal tract (CST) axon regen
Sox11 overexpression mechanism?
Sox11 overexpression: increased CST axon growth
Epigenetic modification mechanism for regenerative neuroscience?
Epigenetic modification: relax histones to let transcription factors access DNA for axonal regeneration (in neurodevelopment histones are relaxed)
PCAF promotes acetylation in the PNS (not CNS)
After injury, retrograde transport of NGF/MEK/ERK activates PCAF
This relaxes histones and accesses pro-regenerative genes (in PCAF overexpression, axons grow past lesion site)
Histone deacetylase inhibitors (HDAC3) mechanism?
Histone deacetylase inhibitors (HDAC3)
Dephosphorylation of HDAC3 reduces its activity
This allows transcription factors to access pro-regenerative genes]- promotes outgrowth of dorsal root ganglion neurons
Goals of regenerative neuroscience?
Inhibit inhibitory signals of axonal growth
Promote pro-regenerative growth signals
Inhibit glial scar formation]- this is neuroprotective for isolating the lesion but is a molecular barrier for regeneration
Replace lost cells
Examples of regenerative success?
- new axons grow around lesion/through lesion
- sprouting from transected axon and preserved axon (e.g. sprouting from lesioned to other supraspinal axons, sprouting to propriospinal relays, sprouting of unlesioned propriospinal axons, sprouting of remaining supraspinal axons -> regeneration)
- distal lesioned axons (Wallerian) degenerates: reconnectivity brings functional recovery
- different regen capacity: PNS> CNS (DCs)> CNS (CST)
