On the role of galectin-4 in (re)myelination and multiple sclerosis

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    Abstract

    On the role of galectin-4 in (re)myelination and multiple sclerosis

    Multiple sclerosis (MS) is the most common demyelinating diseases of the central nervous system (CNS). Remyelination is a regenerative process and is most efficient when recruited oligodendrocyte progenitor cells (OPCs) mature and re-supply the denuded axon with myelin. A tight regulation and cooperative communication between neurons and glial cells contribute to successful remyelination. In MS, cell dysfunction and/or an inhibitory environment leads to impaired differentiation of OPCs into myelinating oligodendrocytes. The persistent loss of neuroprotective and insulating myelin results in neurological deficits and disease progression.

    Previous findings indicate that secreted neuronal galectin-4 negatively regulates the timing of OPC differentiation during development. Using experimental models for de- and/or remyelination, we revealed that neuronal galectin-4 is transiently re-expressed on demyelinated axons, while persistently present on axons in inactive MS lesions. In addition, in the demyelinated areas galectin-4 was present in microglia and macrophages. Whether microglia and macrophages are cellular sources of galectin-4 remains to be determined. Preliminary data indicate that a distinct isoform of galectin-4 may exist in the CNS.

    Surprisingly, in contrast to their individual activities as negative regulators or (re)myelination, our findings indicate that the simultaneous presence of galectin-4 and fibronectin promoted myelin membrane formation. To obtain more insight in the underlying mechanism, we identified at the cell surface of immature oligodendrocytes, two galectin-4 binding sites, UGT8 and contactin-1. UGT8 is an enzyme responsible for the synthesis of the major myelin lipid galactosylceramide. Hence, modulating galectin-4 signaling in MS lesions, among others by modulating its interactions with UGT8 and contactin-1, may be attractive approaches to promote remyelination.
    Original languageEnglish
    QualificationDoctor of Philosophy
    Awarding Institution
    • University of Groningen
    Supervisors/Advisors
    • Baron, Wia, Supervisor
    • Hoekstra, Dick, Supervisor
    Award date8-Nov-2021
    Place of Publication[Groningen]
    Publisher
    DOIs
    Publication statusPublished - 2021

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