Abstract
Myelin sheaths on vertebrate axons provide protection, vital support and increase the speed of neuronal signals. Myelin degeneration can be caused by viral, autoimmune or genetic diseases. Remyelination is a natural process that restores the myelin sheath and, consequently, neuronal function after a demyelination event, preventing neurodegeneration and thereby neuron functional loss. Pharmacological approaches to remyelination represent a promising new frontier in the therapy of human demyelination pathologies and might provide novel tools to improve adaptive myelination in aged individuals. Recent phenotypical screens have identified agonists of the atypical G protein-coupled receptor Smoothened and inhibitors of the glioma-associated oncogene 1 as being amongst the most potent stimulators of oligodendrocyte precursor cell (OPC) differentiation in vitro and remyelination in the central nervous system (CNS) of mice. Here, we discuss the current state-of-the-art of studies on the role of Sonic Hedgehog reactivation during remyelination, referring readers to other reviews for the role of Hedgehog signaling in cancer and stem cell maintenance.
Highlights
The Hedgehog (Hh) signaling pathway is an evolutionary conserved signal transduction pathway that plays a crucial role during embryonic development and tissue regeneration in vertebrates
Advances in our understanding of myelin plasticity in the adult brain have been paralleled by the development of oligodendrocyte cell-based assays allowing for large screens of small molecules with regard to their promyelinating properties [11,12,13,14,15,16,17,18]. These studies identified a number of biologically active drugs with remyelination properties, including glucocorticoids acting as Smo agonists [14,15], imidazole antifungal drugs [14,17], Benztropine, an anticholinergic drug used in the treatment of Parkinson’s disease [12], epidermal growth factor receptor (EGFR) inhibitors [11,15], and sterol regulatory element binding (SREB) factors [18]
How Sonic Hedgehog (Shh) reactivation leads to neural stem cell (NSC) differentiation toward the oligodendrocyte precursor cell (OPC) lineage during remyelination processes is beginning to be clarified [6,35,36,37,38,39,40,41,42,43,48,52] and a number of drugs stimulating Smo activity and remyelination have been selected in large phenotypical screens, aiming at recovering the effects of pathological demyelination in adult brain [11,12,13,14,15,18]
Summary
The Hedgehog (Hh) signaling pathway is an evolutionary conserved signal transduction pathway that plays a crucial role during embryonic development and tissue regeneration in vertebrates. Advances in our understanding of myelin plasticity in the adult brain have been paralleled by the development of oligodendrocyte cell-based assays allowing for large screens of small molecules with regard to their promyelinating properties [11,12,13,14,15,16,17,18] These studies identified a number of biologically active drugs with remyelination properties, including glucocorticoids acting as Smo agonists [14,15], imidazole antifungal drugs [14,17], Benztropine, an anticholinergic drug used in the treatment of Parkinson’s disease [12], epidermal growth factor receptor (EGFR) inhibitors [11,15], and sterol regulatory element binding (SREB) factors [18]. We review the main aspects of Shh signaling reactivation during remyelination and how Smo agonists promote OPC differentiation, taking into consideration recent structural and mechanistic studies on the mechanism of Smo activation
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