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ORIGINAL RESEARCH article

Front. Mol. Neurosci.
Sec. Methods and Model Organisms
Volume 17 - 2024 | doi: 10.3389/fnmol.2024.1473960
This article is part of the Research Topic Molecular pathology, biomarkers and therapeutics of brain tumor and neurodegenerative disease View all 4 articles

Pharmacological targeting of Smoothened receptor cysteine-rich domain by Budesonide promotes in vitro myelination

Provisionally accepted
Antonella D. Recchia Antonella D. Recchia 1Alessandra Dominicis Alessandra Dominicis 1Vincenzo M. D'Amore Vincenzo M. D'Amore 2Tommaso Fabiano Tommaso Fabiano 1,3Aland I. Al Jaf Aland I. Al Jaf 1Simone Peria Simone Peria 1Francesco Basoli Francesco Basoli 4Alberto Rainer Alberto Rainer 4,5Luciana Marinelli Luciana Marinelli 2Francesco Saverio Di Leva Francesco Saverio Di Leva 2*Antonella Ragnini-Wilson Antonella Ragnini-Wilson 1*
  • 1 Department of Biology, University of Rome Tor Vergata, Roma, Lazio, Italy
  • 2 Department of Farmacy, University of Naples “Federico II”, Naples, Italy, Naples, Italy
  • 3 Department of Life Sciences, University of Trieste, Trieste, Friuli-Venezia Giulia, Italy
  • 4 Departmental Faculty of Sciences and Technologies for Sustainable Development and One Health, Campus Bio-Medico University Hospital, Roma, Italy
  • 5 Department of Engineering, Università Campus Bio-Medico di Roma, 00128 Rome, Italy, Rome, Lazio, Italy

The final, formatted version of the article will be published soon.

    The myelin sheath ensures efficient nerve impulse transmission along the axons. Remyelination is a spontaneous process that restores axonal insulation, promoting neuroprotection and recovery after myelin damage. There is an urgent need for new pharmacological approaches to remyelination and to improve the most effective molecules. Some glucocorticoids (GC) were identified through phenotypical screens for their promyelinating properties. These GC compounds share the ability to bind the Smoothened (Smo) receptor of the Hedgehog (Hh) pathway. Gaining a deeper insight into how they modulate Smo receptor activity could guide structure-based studies to leverage the GCs' potent promyelinating activity for a more targeted approach to remyelination. Here we focused on clarifying the mechanism of action of Budesonide, a GC known to bind the Smo cysteine-rich domain (CRD) and prevent Smo translocation to the cilium in fibroblasts. Our study employed a combination of cellular, biochemical and molecular dynamic approaches to show that treating oligodendroglial cells with Budesonide promotes myelination of synthetic axons and reduces Smo CRD conformational flexibility. This inhibits the Smo-mediated canonical signaling while activating the Liver Kinase B1 (LKB1)/AMP-activated protein kinase (AMPK) pathway, leading to Myelin basic protein (MBP) expression. These insights pave the way for pharmacological targeting of Smo CRD to enhance oligodendrocyte precursor cells (OPCs) differentiation and improve remyelination.

    Keywords: remyelination, oligodendrocytes, Glucocorticoids, Molecular Docking & Molecular Dynamics (MD) simulation, Glia cells, Hedgehog (Hh), OPC, drug mechanism of action

    Received: 31 Jul 2024; Accepted: 30 Sep 2024.

    Copyright: © 2024 Recchia, Dominicis, D'Amore, Fabiano, Al Jaf, Peria, Basoli, Rainer, Marinelli, Di Leva and Ragnini-Wilson. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence:
    Francesco Saverio Di Leva, Department of Farmacy, University of Naples “Federico II”, Naples, Italy, Naples, Italy
    Antonella Ragnini-Wilson, Department of Biology, University of Rome Tor Vergata, Roma, 00173, Lazio, Italy

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