PKC Mediates Inhibitory Effects of Myelin and Chondroitin Sulfate Proteoglycans on Axonal Regeneration

Nat Neurosci. 2004 Mar;7(3):261-8. doi: 10.1038/nn1193. Epub 2004 Feb 8.

Abstract

Successful axon regeneration in the mammalian central nervous system (CNS) is at least partially compromised due to the inhibitors associated with myelin and glial scar. However, the intracellular signaling mechanisms underlying these inhibitory activities are largely unknown. Here we provide biochemical and functional evidence that conventional isoforms of protein kinase C (PKC) are key components in the signaling pathways that mediate the inhibitory activities of myelin components and chondroitin sulfate proteoglycans (CSPGs), the major class of inhibitors in the glial scar. Both the myelin inhibitors and CSPGs induce PKC activation. Blocking PKC activity pharmacologically and genetically attenuates the ability of CNS myelin and CSPGs to activate Rho and inhibit neurite outgrowth. Intrathecal infusion of a PKC inhibitor, Gö6976, into the site of dorsal hemisection promotes regeneration of dorsal column axons across and beyond the lesion site in adult rats. Thus, perturbing PKC activity could represent a therapeutic approach to stimulating axon regeneration after brain and spinal cord injuries.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cells, Cultured
  • Central Nervous System / cytology
  • Central Nervous System / growth & development
  • Central Nervous System / injuries
  • Chondroitin Sulfate Proteoglycans / metabolism*
  • Chondroitin Sulfate Proteoglycans / pharmacology
  • Enzyme Inhibitors / pharmacology
  • Female
  • Growth Cones / drug effects
  • Growth Cones / metabolism*
  • Growth Cones / ultrastructure
  • Myelin Proteins / metabolism*
  • Myelin Proteins / pharmacology
  • Myelin-Associated Glycoprotein / metabolism
  • Myelin-Associated Glycoprotein / pharmacology
  • Nerve Regeneration / drug effects
  • Nerve Regeneration / physiology*
  • Neural Pathways / cytology
  • Neural Pathways / growth & development
  • Neural Pathways / metabolism
  • Nogo Proteins
  • Protein Isoforms / antagonists & inhibitors
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Protein Kinase C / antagonists & inhibitors
  • Protein Kinase C / genetics
  • Protein Kinase C / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Recombinant Fusion Proteins / metabolism
  • Recombinant Fusion Proteins / pharmacology
  • Recovery of Function / drug effects
  • Recovery of Function / physiology
  • Repressor Proteins / metabolism*
  • Repressor Proteins / pharmacology
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Spinal Cord / cytology
  • Spinal Cord / growth & development
  • Spinal Cord / metabolism
  • Treatment Outcome

Substances

  • Chondroitin Sulfate Proteoglycans
  • Enzyme Inhibitors
  • Myelin Proteins
  • Myelin-Associated Glycoprotein
  • Nogo Proteins
  • Protein Isoforms
  • Recombinant Fusion Proteins
  • Repressor Proteins
  • Rtn4 protein, rat
  • Protein Kinase C