An inhibitor of chondroitin sulfate proteoglycan synthesis promotes central nervous system remyelination

Michael B. Keough, James A. Rogers, Ping Zhang, Samuel K. Jensen, Erin L. Stephenson, Tieyu Chen, Mitchel G. Hurlbert, Lorraine W. Lau, Khalil S. Rawji, Jason R. Plemel, Marcus Koch, Chang-Chun Ling and V. Wee Yong ()
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Michael B. Keough: Hotchkiss Brain Institute, University of Calgary
James A. Rogers: Hotchkiss Brain Institute, University of Calgary
Ping Zhang: University of Calgary
Samuel K. Jensen: Hotchkiss Brain Institute, University of Calgary
Erin L. Stephenson: Hotchkiss Brain Institute, University of Calgary
Tieyu Chen: University of Calgary
Mitchel G. Hurlbert: Hotchkiss Brain Institute, University of Calgary
Lorraine W. Lau: Hotchkiss Brain Institute, University of Calgary
Khalil S. Rawji: Hotchkiss Brain Institute, University of Calgary
Jason R. Plemel: Hotchkiss Brain Institute, University of Calgary
Marcus Koch: Hotchkiss Brain Institute, University of Calgary
Chang-Chun Ling: University of Calgary
V. Wee Yong: Hotchkiss Brain Institute, University of Calgary

Nature Communications, 2016, vol. 7, issue 1, 1-12

Abstract: Abstract Remyelination is the generation of new myelin sheaths after injury facilitated by processes of differentiating oligodendrocyte precursor cells (OPCs). Although this repair phenomenon occurs in lesions of multiple sclerosis patients, many lesions fail to completely remyelinate. A number of factors have been identified that contribute to remyelination failure, including the upregulated chondroitin sulfate proteoglycans (CSPGs) that comprise part of the astrogliotic scar. We show that in vitro, OPCs have dramatically reduced process outgrowth in the presence of CSPGs, and a medication library that includes a number of recently reported OPC differentiation drugs failed to rescue this inhibitory phenotype on CSPGs. We introduce a novel CSPG synthesis inhibitor to reduce CSPG content and find rescued process outgrowth from OPCs in vitro and accelerated remyelination following focal demyelination in mice. Preventing CSPG deposition into the lesion microenvironment may be a useful strategy to promote repair in multiple sclerosis and other neurological disorders.

Date: 2016
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DOI: 10.1038/ncomms11312

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