Flashcards in L20: Mechanisms of Neurodegeneration & Regeneration Deck (18):
Why is the repair of the damaged nervous system limited?
Neurons are not easily saved or repaired. They are irreparably damaged. Also, the immediate cellular environment is a barrier
What are the 4 main things we must have for effective nerve regeneration?
1. survival of the nerve cell body
2. clearance of the damaged distal axon, myelin, breakdown products, and other debris
3. an environment that stimulates new axonal regrowth
4. guidance cues for the axon to find its original cellular target
Briefly explain the process of neuronal repair in the PNS if and when the cell body of the nerve is still intact.
-injury to peripheral nerve (cell body is intact)
-process of wallerian degeneration starts quickly (1 week), recruiting macrophages & schwann cells clean up the debris (distal axonal fragments & other damaged tissue)
-schwann cells will also be secreting neurotrophins
-injured axons will form growth cones & begin to regenerate
-guidance molecules get axons to target site
In the PNS, how long does it take axons to regrow?
It depends on the distance it needs to travel (1 inch/month)
nerve cut vs nerve crush
nerve cut is harder to repair than nerve crush
-in nerve cut, axons need to re-grow; start seeing growth cones
-in nerve crush, still remaining surviving axons can re-establish connections
*both cases need to remove debris & provide environment to stimulate new connections.
What is the key to successful regeneration in the periphery?
schwann cells b/c they promote axonal regeneration via different factors and provide laminin
What provides the guidance cues in the periphery to aid in taking axons to the target?
the bands of bungner will take the axon to the target
Why is neuronal repair in CNS less effective than PNS?
b/c even if the cell body is intact, CNS doesn't have the 3 other main required things: degeneration of debris, an environment that stimulates new axonal growth, guidance cues
Similar to repair in the PNS, in the CNS, wallerian degeneration occurs quickly (macrophages are recruited to clean up distal axonal debris, myelin breakdown), but why is wallerian degeneration VERY INEFFECTIVE in CNS?
In CNS, oligodendrocytes don't help with cleaning up (unlike in PNS, the schwann cells do a lot). There debris clearance is slow and incomplete.
Why is debris clearance so important in both PNS and CNS repair?
Myelin breakdown products are inhibitory to regrowth creating hostile environment.
Explain how the formation of glial scars by astrocytes and microglia creates the hostile environment impeding CNS repair.
-astrocytes & microglia become active, proliferate and will produce glial scar = physical & chemical barrier to nerve regeneration (this is a natural process that happens in the CNS to limit tissue damage)
-glial scar can lead to a cyst = physical barrier to nerve regeneration
-glial scar is made of large molecules called chondroitin sulfate proteoglycans (CSPGs), which axons DO NOT LIKE
Any type of injury can produce proteogylcans. What kind of effect do proteoglycans have on neuronal regrowth?
In PNS repair, schwann cells secrete laminin and neurotrophins, which will promote regrowth. In CNS, the molecules that are secreted are actually inhibitory to growth. List them.
-chondroitin sulfate proteoglycans (CSPGs)
List the 5 general strategies that can be used to repair the damaged nervous system
1) biomaterials -can be devised to provide growth promoting substrate
2) growth factor targets
3) Agents that will change the local environment
4) agents to promote remyelination after injury
5) placement therapy to replace neurons or oligodendrocytes
Of the 5 general strategies to repair damaged nervous system, what do peripheral nerve grafts do?
Peripheral nerve grafts can be used in PNS or CNS repair. They provide a source of growth factors and provide a permissive substrate on which axons can easily grow.
Of the 5 general strategies to repair damaged nervous system, what do Chondroitinase ABC do?
Chondroitinase ABC is an enzyme that can degrade sugars. It removes sugars of proteoglycans, leaving the protein core. The protein core itself is not inhibitory to regrowth. Hence, using this enzyme will create a permissive environment for regrowth. Also, removing the sugars can free up space for oligodendrocytes to re-myelinate.
Of the 5 general strategies to repair damaged nervous system, what do cell replacement therapies do?
using stem cells to turn into neurons. In brain there are stem cells but they are quiescent. Other stem cell sources: embryonic stem cells, adult stem cells, neural stem cells, and reprogrammed cells from other tissues. To successfully restore function, a stem cell will have to differentiate into appropriate kind of neuron, make connections w/ appropriate target cells, form working synapses.