Ways of Inducing Axonal Regrowth in the CNS after injury: Flashcards
Compare the regeneration capacity in CNS versus PNS:
PNS Environment:
- contain Schwann cells which are potent promoters of neurone outgrowth
- Schwann cells produce growth promoting factors such as NGF
- ECM is rich in in growth-promoting molecules like laminin and fibronectin, supporting axonal growth
- proliferate and form empty endoneural tubes in which growth cones can act as feelers which CNS doesn’t have
- Immune response: macrophages clear myelin debris providing the right conditions for regeneration
CNS Environment:
- contain oligodendrocytes (myelinating cells of CNS) which lack the capacity to support axonal regrowth
- also central myelin is a potent inhibitor of axon outgrowth
- CNS white matter is selectively inhibitory for axonal growth
- laminin and fibronectin are no longer expressed and thus important adhesion molecules are absent from the regenerating environment
- forms glial scars and contains inhibitory molecules (CSPGs) hindering axonal extension
Key differences:
- As opposed as PNS neurones, epigenetic changes leading to neuronal expression of regeneration-associated genes (RAGs) upon axon injury is limited in CNS
- Growth-associated protein 43 (GAP-43) is lost in CNS neurones in adults but retained in PNS neurones
- High expression of proteins suppressing axonal growth in CNS neurons (PTEN,
SOCS3, EFA-6)
Describe NOGO as an inhibitor of axonal growth:
Located in the endoplasmic reticulum of oligodendrocytes but not Schwann cells
Has 3 isoforms - NOGO-A, B and C
Has 2 inhibitory domains - amino Nogo (only found in Nogo-A + NOGO-66
Nogo-A (NI-250) is the most inhibitory because it has 2 inhibitory domains and not can flip between them
NOGO-A is a membrane protein that inhibits axonal growth by interacting with NOGO receptors
Describe CSPG as an inhibitor of axonal growth:
Chondroitin Sulphate Proteoglycans:
Family of molecules with a protein core and negatively charged Glycosaminoglycans (GAGs) attached (electrostatically repellent for growth cones)
Released by hypertrophic, reactive phenotypic astrocytes found in the glial scar
CSPGs are re-expressed after injury in the brain and spinal cord
CSPGs bind to many receptors (LAR, PTPsigma, NGR) ultimately activating ROCK resulting in actin depolymerisation so inhibition of axon growth.
Describe the effect of glial scarring:
After injury CSGP expression is rapidly up-regulated by reactive astrocytes
This forms an inhibition gradient
highest concentration of inhibitory molecules is at the centre of the lesion
Astrocytes proliferate and form a dense scar tissue post injury, releasing inhibitory molecules and creating a physical barrier to axonal regeneration
What are the secondary changes that occur after injury ?
Astrocyte proliferation
Activation of microglia
Formation of a glial scar
Inflammation
Invasion by immune cells
Proliferation of oligodendrocyte precursor cells
Describe the intrinsic factors which inhibit axonal growth:
Neuronal growth potential - adult CNS neurones diminished intrinsic capacity for axonal growth compared to developing neurones
PTEN/mTOR Pathway - Phosphatase and Tensin Homolog (PTEN) negatively regulates the mTOR pathway, which is crucial for protein synthesis and axonal growth
SOCS3/STAT3 Pathway - Suppressor of Cytokine Signaling 3 (SOCS3) inhibits the JAK/STAT pathway, reducing the regenerative response
Why is CNS regeneration poor ?
Extrinsic (environmental) factors:
- low concentration of neurotrophins and no Schwann cells
- no endoneural tube formation due to no Schwann cells
- Myelin is a potent inhibitor of axon growth (constitutively expressed MAIs: NogoA, MAG, OMgp)
- formation of glial scar, secretion of CSPGs by reactive astrocytes upregulated by injury
- MAIs & CSPGs bind to receptors on CNS axons which activate ROCK —» actin depolymerisation
- inflammation + immune reactions
Intrinsic Factors:
- limited epigenetic changes favouring axonal growth upon axon injury (no phenotype change)
- high expression of proteins inhibiting axon growth
Discuss the requirements for the structural and functional recovery of injured axons:
Neuronal survival - post injury, the preservation of neuronal cell bodies is essential to maintain the potential for regeneration
Axonal Regrowth - damaged axons must extend new processes to re-establish connections with their original targets
Guidance cues - axons require precise molecular signals to navigate through CNS to reach target
Synaptic formation - Re-establishment of functional synapses is crucial for restoring neural circuitry and functional recovery
Re-myelination - ensures proper conduction velocities are restored
Describe the extrinsic factors which inhibit axonal growth:
Myelin Associated Inhibitors:
- NOGO-A inhibits axial growth by interacting with NgR receptors
- Oligodendrocyte Myelin Glycoprotein (OMgp) interacts with NgR to inhibit neurone outgrowth
- Myelin-Associated Glycoprotein (MAG) binds to NgR and other receptors, leading to growth cone collapse
CSGPs - Components of the ECM that inhibit axonal extension by interacting with receptors like Protein Tyrosine Phosphatase Sigma (PTPσ).
Glial scarring - Astrocytes proliferate and form a dense scar tissue post-injury, releasing inhibitory molecules and creating a physical barrier to axonal regeneration
Describe neural grafts as a method for axonal regrowth:
Provide a source of depleted substance
Stimulate neurone growth and promotes survival of neurones
Replace lost structures in brain and spinal cord
Materials for neural graft:
- tissue from foetal CNS
- tissue from PNS
- peripheral autonomic neurones
- tissue from outside nervous system
- isolated, cultured or genetically engineered cells
