Chondroitin sulfate proteoglycans inhibit oligodendrocyte myelination through PTPσ

CNS damage often results in demyelination of spared axons due to oligodendroglial cell death and dysfunction near the injury site. Although new oligodendroglia are generated following CNS injury and disease, the process of remyelination is typically incomplete resulting in long-term functional defic...

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Bibliographic Details
Published in:Experimental neurology 2013-09, Vol.247, p.113-121
Main Authors: Pendleton, James C., Shamblott, Michael J., Gary, Devin S., Belegu, Visar, Hurtado, Andres, Malone, Misti L., McDonald, John W.
Format: Article
Language:English
Subjects:
Aggrecans - pharmacology
Animals
Animals, Newborn
Antigens - pharmacology
Biological and medical sciences
Cell Differentiation - drug effects
Cells, Cultured
Chondroitin ABC Lyase - pharmacology
Chondroitin Sulfate Proteoglycans - pharmacology
CSPG
Demyelination
Ganglia, Spinal - cytology
Gangliosides - metabolism
Gene Expression Regulation - drug effects
Injuries of the nervous system and the skull. Diseases due to physical agents
Medical sciences
Myelin Basic Protein - metabolism
Myelin Sheath - drug effects
Neurofilament Proteins - metabolism
Neurology
Oligodendrocyte progenitor cell
Oligodendroglia - drug effects
Protein tyrosine phosphatase
Proteoglycans - pharmacology
Rats
Rats, Sprague-Dawley
Receptor-Like Protein Tyrosine Phosphatases, Class 2 - metabolism
rho-Associated Kinases - metabolism
RNA, Small Interfering - metabolism
Signal Transduction - drug effects
Stem Cells
Traumas. Diseases due to physical agents
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Summary:CNS damage often results in demyelination of spared axons due to oligodendroglial cell death and dysfunction near the injury site. Although new oligodendroglia are generated following CNS injury and disease, the process of remyelination is typically incomplete resulting in long-term functional deficits. Chondroitin sulfate proteoglycans (CSPGs) are upregulated in CNS grey and white matter following injury and disease and are a major component of the inhibitory scar that suppresses axon regeneration. CSPG inhibition of axonal regeneration is mediated, at least in part, by the protein tyrosine phosphatase sigma (PTPσ) receptor. Recent evidence demonstrates that CSPGs inhibit OL process outgrowth, however, the means by which their effects are mediated remains unclear. Here we investigate the role of PTPσ in CSPG inhibition of OL function. We found that the CSPGs, aggrecan, neurocan and NG2 all imposed an inhibitory effect on OL process outgrowth and myelination. These inhibitory effects were reversed by degradation of CSPGs with Chondroitinase ABC prior to OL exposure. RNAi-mediated down-regulation of PTPσ reversed the inhibitory effect of CSPGs on OL process outgrowth and myelination. Likewise, CSPG inhibition of process outgrowth and myelination was significantly reduced in cultures containing PTPσ−/− OLs. Finally, inhibition of Rho-associated kinase (ROCK) increased OL process outgrowth and myelination during exposure to CSPGs. These results suggest that in addition to their inhibitory effects on axon regeneration, CSPGs have multiple inhibitory actions on OLs that result in incomplete remyelination following CNS injury. The identification of PTPσ as a receptor for CSPGs, and the participation of ROCK downstream of CSPG exposure, reveal potential therapeutic targets to enhance white matter repair in the damaged CNS. •CSPGs inhibit the ability of oligodendrocytes (OL) to myelinate.•CSPG-mediated inhibition of myelination is not simply a result of reduced in OL process outgrowth.•CSPG-mediated inhibition of both OL process outgrowth and myelination is PTPσ-dependent.•Reduced PTPσ expression led to a reversal of the CSPG-mediated inhibition of myelination.•The Rho-associated kinase (ROCK) inhibitor reversed CSPG-mediated inhibition of myelination.
ISSN:0014-4886
1090-2430
DOI:10.1016/j.expneurol.2013.04.003