Nerve Injury & Regeneration (Theme D) Flashcards
What are the 2 factors that determine the ability of an axon to regenerate?
- The intrinsic capacity of the neurone to build a new axon
- The growth-permissiveness of the axonal environment
When axons are injured, which part of it dies?
The distal part
The axonal environment is a major determinant of regeneration.
What is the difference between the growth-permissiveness of the CNS and the PNS?
The PNS is permissive, the CNS is (actively) inhibitory
Axonal regeneration depends on the location of:
1. The injury
2. The cell body
Axonal regeneration depends on the location of the injury, NOT the location of the cell body
What is the name of the response that enables axons to regenerate in the PNS?
The Schwann cell injury response
Describe the process of the Schwann cell injury response (which occurs in the PNS)
- Injury causes axonal degeneration
- Triggers the reprogramming & radical phenotypic change of Myelin & Remak (non-myelin) Schwann cells in the PNS
- Which form REPAIR SCHWANN CELLS which are specialised to support repair
- After nerve regeneration, Repair Schwann cells undergo reverse reprogramming - axonal signals convert them back to Myelin & Remak Schwann cells
In peripheral nerves, there are 2 types of Schwann cells. What are they called and what is the difference between them?
- Myelin Schwann cell
- Remak Schwann cell (non-myelin)
Describe the process by which Repair Schwann cells are formed from Schwann cells (myelin & remak) in the PNS
- Axon degeneration (loss of axonal contact) denervates Schwann cells
- This triggers them to elongate (x2-3 fold), branch and form compact columns (repair Schwann cells)
- These are regeneration tracts - which provide strong regeneration support and guide axons back to their targets
What is the name given to the regenerating nerve?
The ‘distal stump’
How do neurones build axons?
- In ‘growth mode’, growth cones guide growing axons to their targets in the embryo
- New material to build the axon (from the cell body), is supplied by axonal transport & local synthesis
a. Anterograde transport (body -> terminal), via kinesin
b. Retrograde transport (terminal -> body), via dynein
Compare anterograde & retrograde axonal transport
- Anterograde transport = body -> terminal, uses kinesin
- Retrograde transport = terminal -> body, uses dynein
What happens to the growth cone after development?
From development -> the adult
Neurones switch from ‘growth mode’ -> ‘transmitting mode’
The growth cone turns into an axon terminal
Axons regenerate very slowly. What is the problem with this?
Axons grow ~1mm / day
During this time more distal repair cells are chronically denervated
During chronic denervation, repair cells deteriorate & become dysfunctional - reducing support for regenerating axons (this can be seen experimentally - as a loss of differentiation markers)
Peripheral nerves have very strong regenerative potential. But in larger animals / humans, nerve injuries remain a serious problem, due to:
- Deterioration of chronically denervated Repair cells
- Axons get lost along the way and innervate the wrong targets
- The target atrophies and degenerates
- Neurones fail to maintain the growth mode (and go into transmitting mode)
Give 3 examples of regeneration associated genes (RAGs)
- c-Jun
- STAT3
- CNTF
What are the injury responses of the CNS glial cells?
- Astrocytes proliferate & enlarge (form the glial scar)
- Microglia become activated & migrate to injury site (act as the immune cells of the CNS - carry out phagocytosis & release growth factors)
- Oligodendrocytes fail to break down myelin - causing build up of myelin debris in the CNS environment, which inhibits axonal regeneration (myelin contains inhibitory molecules)
What is the glial scar?
A complex structure formed by glial cells, particularly astrocytes, in response to injury / damage in the CNS.
However, the scar has both +ve & -ve properties in the context of CNS regeneration.
What are the adaptive properties (+ve) of the glial scar in terms of CNS regeneration?
Isolates the injury site
Release of growth factors that stimulate regeneration
Experimental prevention of the glial scar formation demonstrates that it has some useful properties - how?
Experimental prevention of the glial scar formation results in:
a. Inc inflammation
b. Inc neuronal death, axon die-back & demyelination
c. Preventing the scar formation does not promote regeneration
What are the maladaptive (-ve) properties of the glial scar in terms of CNS regeneration?
Inhibits axonal regeneration: releases inhibitory molecules
E.g.,
- Chrondroitin sulphate proteoglycans (CSPG)
- Myelin molecules (MAG, Omg)
- Nogo
Formation of a glial seal can prevent axonal penetration & therefore formation of neuronal connections
Promoting axonal growth is a potential way to improve CNS regeneration. How could this be done?
Activate pro-growth signalling pathways in neurones
E.g., - by activating mTOR, cAMP pathways
E.g., - by increasing electrical activity in neurones
Inhibit inhibitory molecules
E.g., - by chondroitinase ABC
Stabilise microtubules to promote growth cone formation
I.e., through drugs (pharmaceutical intervention)
Building a bridge across the injury is one potential way to improve CNS regeneration. Give an example of a molecule that could be used for this
Sch
Injecting embryonic neurones could be a potential way to improve CNS regeneration. Why is this?
Embryonic neurones regenerate in the CNS, and form correct synaptic connections
This is because they don’t have receptors for the inhibitors present in the CNS environment
*However, this system is a bit uncontrolled (limitation)
The Schwann cell injury response at the molecular level activates ‘the repair program’. What does this involve?
- Upregulation of trophic factors (growth factors) & cell adhesion molecules
- Myelin breakdown - important to breakdown redundant myelin sheaths as myelin-associated molecules inhibit axon growth
- Axon guidance - formation of regeneration tracks which direct axons to their target
Why is it important that redundant myelin material is broken down in the context of axonal regeneration?
Myelin-associated molecules inhibit axon growth
Give 6 examples of trophic (growth) factors that are upregulated as a result of the Schwann cells injury response
GDNF
BDNF
NGF
N-cadherin
NCAM
Netrin
