PKC mediates inhibitory effects of myelin and chondroitin sulfate proteoglycans on axonal regeneration.
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.
Sivasankaran
Rajeev
R
Division of Neuroscience, 320 Longwood Avenue, Children's Hospital, Boston, Massachusetts 02115, USA.
Pei
Jiong
J
Wang
Kevin C
KC
Zhang
Yi Ping
YP
Shields
Christopher B
CB
Xu
Xiao-Ming
XM
He
Zhigang
Z
D000818:Animals; D002478:Cells, Cultured; D002490:Central Nervous System / Q000166:cytology / Q000254:growth & development / Q000293:injuries; D011508:Chondroitin Sulfate Proteoglycans / Q000378:metabolism* / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D020439:Growth Cones / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D009185:Myelin Proteins / Q000378:metabolism* / Q000494:pharmacology; D018992:Myelin-Associated Glycoprotein / Q000378:metabolism / Q000494:pharmacology; D009416:Nerve Regeneration / Q000187:drug effects / Q000502:physiology*; D009434:Neural Pathways / Q000166:cytology / Q000254:growth & development / Q000378:metabolism; D000070798:Nogo Proteins; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011993:Recombinant Fusion Proteins / Q000378:metabolism / Q000494:pharmacology; D020127:Recovery of Function / Q000187:drug effects / Q000502:physiology; D012097:Repressor Proteins / Q000378:metabolism* / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013116:Spinal Cord / Q000166:cytology / Q000254:growth & development / Q000378:metabolism; D016896:Treatment Outcome
D011508:Chondroitin Sulfate Proteoglycans; D004791:Enzyme Inhibitors; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; D000070798:Nogo Proteins; D020033:Protein Isoforms; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; C000603197:Rtn4 protein, rat; D011493:Protein Kinase C