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Brain 2009 132(2):465-481; doi:10.1093/brain/awn334
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© 2009 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Myelin-mediated inhibition of oligodendrocyte precursor differentiation can be overcome by pharmacological modulation of Fyn-RhoA and protein kinase C signalling

Alexandra S. Baer1,*, Yasir A. Syed1,*, Sung Ung Kang2,*, Dieter Mitteregger1, Raluca Vig2, Charles ffrench-Constant3, Robin J. M. Franklin4, Friedrich Altmann5, Gert Lubec2 and Mark R. Kotter1,6

1 Department of Neurosurgery, Medical University Vienna, Vienna, Austria 2 Department of Pediatrics, Medical University Vienna, Vienna, Austria 3 MS Society/University of Edinburgh Centre for Translational Research, Centre for Inflammation Research, The Queen's Medical Research Institute, Edinburgh, UK 4 Cambridge Centre for Brain Repair and Department of Veterinary Medicine, University of Cambridge, Cambridge, UK 5 University of Natural Resources and Applied Life Sciences Vienna, Vienna, Austria 6 Department of Neurosurgery, Georg-August University, Goettingen, Germany

Correspondence to: Dr Mark R. Kotter, Max Planck Institute for Experimental Medicine and Department of Neurosurgery, Georg-August University Goettingen, 37075 Goettingen, Germany E-mail: mark.kotter{at}med.uni-goettingen.de

Failure of oligodendrocyte precursor cell (OPC) differentiation contributes significantly to failed myelin sheath regeneration (remyelination) in chronic demyelinating diseases. Although the reasons for this failure are not completely understood, several lines of evidence point to factors present following demyelination that specifically inhibit differentiation of cells capable of generating remyelinating oligodendrocytes. We have previously demonstrated that myelin debris generated by demyelination inhibits remyelination by inhibiting OPC differentiation and that the inhibitory effects are associated with myelin proteins. In the present study, we narrow down the spectrum of potential protein candidates by proteomic analysis of inhibitory protein fractions prepared by CM and HighQ column chromatography followed by BN/SDS/SDS–PAGE gel separation using Nano-HPLC-ESI-Q-TOF mass spectrometry. We show that the inhibitory effects on OPC differentiation mediated by myelin are regulated by Fyn-RhoA-ROCK signalling as well as by modulation of protein kinase C (PKC) signalling. We demonstrate that pharmacological or siRNA-mediated inhibition of RhoA-ROCK-II and/or PKC signalling can induce OPC differentiation in the presence of myelin. Our results, which provide a mechanistic link between myelin, a mediator of OPC differentiation inhibition associated with demyelinating pathologies and specific signalling pathways amenable to pharmacological manipulation, are therefore of significant potential value for future strategies aimed at enhancing CNS remyelination.

Key Words: adult stem/precursor cells; oligodendrocyte; differentiation; myelin inhibitors; intracellular signalling; multiple sclerosis; remyelination

Abbreviations: MARCKS, Myristoylated, alanine-rich C-kinase substrate; MBP, myelin basic protein; MPEs, myelin protein extracts; OPC, oligodendrocyte precursor cells; PKC, protein kinase C; PLL, polylysine; 3DE, Three dimensional electrophoresis

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Received March 5, 2008. Revised September 7, 2008. Accepted November 12, 2008.

*These authors contributed equally to this work.


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[Abstract] [Full Text] [PDF]


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