The central nervous system (CNS) projection neurons do not regenerate after axonal injury or degeneration.
Several intra-
and extra-cellular factors have been discovered that regulate axon
regeneration. However, it is still difficult to find mechanisms to bypass
extracellular inhibitors associated with glial scar and myelin formation (e.g.,
Cspg, Mag, NogoA, OMgp,
Semaphorins) and help regenerate
a complete axon.
As the CNS matures, the retinal ganglion
cells (RGCs) lose their ability for intrinsic axon growth. This happens with a
change in the initial axonal preference for an extracellular matrix (ECM)
substrate to grow, conferred by integrin α and β heterodimers. Changes in the
extracellular environment compromise the function of neuronal integrin subunit
expression and axonal growth following injury or other deleterious events.
Lukomska and colleagues found that an ECM
substrate fibronectin (Fn) which interacts with integrins was excessively
present in some RGCs that survived optic nerve crush injury. It was found that Fn
promotes survival and axon regeneration of axotomized adult RGCs in culture
without glial scar inhibitors.
Injury-activated macrophages/microglia
upregulate Fn. These cells are recruited by axon regeneration-promoting
zymosan. This increases the Fn levels in the injured area.
The researchers found that Fn’s RGD motif,
which interacts with Itga5 and ItgaV promotes
long-term survival and long-distance axonal regeneration of adult RGCs. Some of
the axons were found to reach the optic chiasm when co-treated with rpl7a gene
therapy.
In conclusion, augmenting Fn levels in the
damaged CNS is a promising therapeutic neuroprotective and neuroregenerative
approach.
REFERENCE:
Lukomska A, Rheaume BA, Frost MP, Theune
WC, Xing J, Damania A, Trakhtenberg EF. Augmenting fibronectin levels in
injured adult CNS promotes axon regeneration in vivo. Exp Neurol. 2024
Sep;379:114877. doi: 10.1016/j.expneurol.2024.114877. Epub 2024 Jun 27. PMID:
38944331; PMCID: PMC11283980.
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