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Polysialylation at Early Stages of Oligodendrocyte Differentiation Promotes Myelin Repair

Werneburg, Sebastian ; Fuchs, Hazel L.S ; Albers, Iris ; Burkhardt, Hannelore ; Gudi, Viktoria ; Skripuletz, Thomas ; Stangel, Martin ; Gerardy-Schahn, Rita ; Hildebrandt, Herbert

The Journal of neuroscience, 2017-08-23, Vol.37 (34), p.8131-8141 [Peer Reviewed Journal]

United States: Society for Neuroscience

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  • Title:
    Polysialylation at Early Stages of Oligodendrocyte Differentiation Promotes Myelin Repair
  • Author/Creator: Werneburg, Sebastian ; Fuchs, Hazel L.S ; Albers, Iris ; Burkhardt, Hannelore ; Gudi, Viktoria ; Skripuletz, Thomas ; Stangel, Martin ; Gerardy-Schahn, Rita ; Hildebrandt, Herbert
  • Publisher: United States: Society for Neuroscience
  • Language: English
  • Subjects: Embryonic Stem Cells - metabolism ; Motor Activity - physiology ; Oligodendroglia - metabolism ; Humans ; Mice, Inbred C57BL ; Cells, Cultured ; CD56 Antigen - biosynthesis ; Male ; Neural Cell Adhesion Molecule L1 ; Sialic Acids - biosynthesis ; Random Allocation ; Demyelinating Diseases - metabolism ; Mice, Knockout ; Myelin Sheath - metabolism ; Animals ; Sialyltransferases - biosynthesis ; Mice ; Cell Differentiation - physiology ; Index Medicus ; polysialic acid ; polysialyltransferases ; developmental myelination ; oligodendrocyte precursors ; PSA-NCAM ; demyelinating diseases
  • Is Part Of: The Journal of neuroscience, 2017-08-23, Vol.37 (34), p.8131-8141
  • Description: Polysialic acid is a glycan modification of the neural cell adhesion molecule (NCAM) produced by the polysialyltransferases ST8SIA2 and ST8SIA4. Polysialic acid has been detected in multiple sclerosis plaques, but its beneficial or adverse role in remyelination is elusive. Here, we show that, despite a developmental delay, myelination at the onset and during cuprizone-induced demyelination was unaffected in male or mice. However, remyelination, restoration of oligodendrocyte densities, and motor recovery after the cessation of cuprizone treatment were compromised. Impaired differentiation of NCAM- or ST8SIA2-negative oligodendrocyte precursors suggested an underlying cell-autonomous mechanism. In contrast, premature differentiation in ST8SIA4-negative cultures explained the accelerated remyelination previously observed in mice. mRNA profiling during differentiation of human stem cell-derived and primary murine oligodendrocytes indicated that the opposing roles of ST8SIA2 and ST8SIA4 arise from sequential expression. We also provide evidence that potentiation of ST8SIA2 by 9- retinoic acid and artificial polysialylation of oligodendrocyte precursors by a bacterial polysialyltransferase are mechanisms to promote oligodendrocytic differentiation. Thus, differential targeting of polysialyltransferases and polysialic acid engineering are promising strategies to advance the treatment of demyelinating diseases. The beneficial or adverse role of polysialic acid (polySia) in myelin repair is a long-standing question. As a modification of the neural cell adhesion molecule (NCAM), polySia is produced by the polysialyltransferases ST8SIA2 and ST8SIA4. Here we demonstrate that NCAM and ST8SIA2 promote oligodendrocyte differentiation and myelin repair as well as motor recovery after cuprizone-induced demyelination. In contrast, ST8SIA4 delays oligodendrocyte differentiation, explaining its adverse role in remyelination. These opposing roles of the polysialyltransferases are based on different expression profiles. 9- retinoic acid enhances ST8SIA2 expression, providing a mechanism for understanding how it supports oligodendrocyte differentiation and remyelination. Furthermore, artificial polysialylation of the cell surface promotes oligodendrocyte differentiation. Thus, boosting ST8SIA2 and engineering of polySia are promising strategies for improving myelin repair.
  • Notes: 1529-2401
    H.L.S. Fuchs' present address: Technische Universität Braunschweig, Institute for Biochemistry, Biotechnology and Bioinformatics, Spielmannstrasse 7, 38106 Braunschweig, Germany.
    Author contributions: S.W., M.S., R.G.-S., and H.H. designed research; S.W., H.L.S.F., I.A., H.B., V.G., and T.S. performed research; S.W., H.L.S.F., H.B., and H.H. analyzed data; S.W. and H.H. wrote the paper.
    S. Werneburg's present address: Department of Neurobiology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655.
  • Identifier: ISSN: 1529-2401
    ISSN: 0270-6474
    EISSN: 1529-2401
    DOI: 10.1523/jneurosci.1147-17.2017
    PMID: 28760868