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Myelin-mediated inhibition of oligodendrocyte precursor differentiation can be overcome by pharmacological modulation of Fyn-RhoA and protein kinase C signalling
Open accessAbstract
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.
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“This was expected as with the culture conditions applied, inhibition of PKCα only shows effects in the presence of inhibitory myelin substrates22.”
From Tamoxifen accelerates the repair of demyelinated lesions in the central nervous system (2016) · cites this paper as [22]
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“Conversely, in the presence of myelin debris, the inhibition of PKCα neutralizes myelin-associated inhibitors and promotes differentiation22.”
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“One critical role for microglia during demyelination is the clearance of myelin debris, which acts as an inhibitor of remyelination [192–194].”
From Oligodendrocyte death and myelin loss in the cuprizone model: an updated overview of the intrinsic and extrinsic causes of cuprizone demyelination (2022) · cites this paper as [193]
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“Our results also confirm previous reports22 that the inhibition of PKCs does not promote differentiation by itself when cells are cultured in serum containing media.”
From Tamoxifen accelerates the repair of demyelinated lesions in the central nervous system (2016) · cites this paper as [22]
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Metadata
- Authors
- Baer, A. S., Syed, Y. A., Kang, S. U., Mitteregger, D., Vig, R., ffrench-Constant, C., Franklin, R. J. M., Altmann, F., Lubec, G., & Kotter, M. R.
- Affiliations
- Medical University of Vienna (AT)
- University of Cambridge (GB)
- Corresponding author
- Kotter, Mark R.
- Venue
- Brain
- Publisher
- Oxford University Press (OUP)
- Published
- 2009-02
- Volume
- 132
- Issue
- 2
- Pages
- 465-481
- ISSN
- 0006-8950 (ISSN-L)
- 1460-2156
- PMC
- PMC2640211
- OpenAlex
- W2159729185
- Cited by
- 211
- References
- 91
- Citations by year
- 2026: 6 · 2025: 13 · 2024: 13 · 2023: 12 · 2022: 16 · 2021: 12 · 2020: 5 · 2019: 8 · 2018: 10 · 2017: 12 · 2016: 14 · 2015: 14 · 2014: 8 · 2013: 19 · 2012: 13
- FWCI
- 5.13
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- cc-by-nc
- Locations
- Brain (publishedVersion)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
- MPG.PuRe (Max Planck Society) (submittedVersion, other-oa)
- Max Planck Institute for Plasma Physics (submittedVersion)
- GRO (submittedVersion)
- UEA Digital Repository (University of East Anglia) (submittedVersion)
- Funders
- Austrian Science Fund
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Health Sciences › Medicine › Clinical Neurology › Multiple Sclerosis Research Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- myelin, remyelination, demyelinating disease, myelin debris, proteomics, siRNA knockdown, pharmacological modulation, myelin proteins
- MeSH terms
- Animals, Animals, Newborn, Carbazoles, Cell Differentiation, Demyelinating Diseases, Electrophoresis, Polyacrylamide Gel, Indoles, Maleimides, Myelin Sheath, Nerve Regeneration, Oligodendroglia, Stem Cells, Signal Transduction, Rats, Sprague-Dawley, 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine, rhoA GTP-Binding Protein, RNA, Small Interfering, Proto-Oncogene Proteins c-fyn, Rats, Protein Kinase C-alpha, rho-Associated Kinases
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