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Paxillin phosphorylation counteracts proteoglycan-mediated inhibition of axon regeneration

Tomoharu Kuboyama1, Xueting Luo, Kevin Park

  • 1Laboratory for Neuronal Growth Mechanisms, RIKEN Brain Science Institute, Wako, Saitama 351-0198, Japan; Division of Neuromedical Science, Institute of Natural Medicine, University of Toyama, Toyama, Toyama 930-0194, Japan.

Experimental Neurology
|June 26, 2013
PubMed

Insights

Protein kinase A (PKA) inhibition reactivates stalled axon endballs by altering paxillin phosphorylation, promoting migration and growth after central nervous system injury. This finding offers a potential therapeutic strategy for axon repair.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Regenerative Medicine

Background:

  • Axon injury in the adult central nervous system leads to endball formation and migration failure.
  • Inhibitory proteoglycans, like aggrecan, impede axon regeneration by halting endball migration.
  • The intracellular mechanisms governing endball migration failure are not well understood.

Purpose of the Study:

  • To investigate the role of protein kinase A (PKA) and paxillin in mediating axon endball migration failure.
  • To explore therapeutic strategies for promoting axon regeneration after central nervous system injury.

Main Methods:

  • Utilized dissociated cultures of adult rat dorsal root ganglion neurons.
  • Examined PKA activation and paxillin phosphorylation in endballs exposed to aggrecan gradients.
  • Applied pharmacological inhibition of PKA and manipulated paxillin expression.
  • Assessed endball migration in vitro and axon regeneration after optic nerve crush in vivo.

Main Results:

  • PKA is activated in endballs on aggrecan gradients, contributing to migration arrest.
  • Pharmacological inhibition of PKA promotes axon growth on aggrecan gradients, likely via paxillin phosphorylation at serine 301.
  • PKA inhibition restores migration of pre-formed endballs by increasing adhesive point contact turnover.
  • Expression of phosphomimetic paxillin rescues aggrecan-mediated growth arrest and facilitates in vivo axon regeneration.

Conclusions:

  • Adhesion dynamics, regulated by PKA and paxillin phosphorylation, are crucial for restoring endball migration.
  • Targeting PKA and paxillin phosphorylation presents a promising therapeutic approach for axon tract repair.
Keywords:
AggrecanAxon regenerationDystrophic endballOptic nervePaxillinPoint contactProtein kinase Ap21-activated kinase

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