Targeting Smoothened as a New Frontier in the Functional Recovery of Central Nervous System Demyelinating Pathologies

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.

Keywords: drug screening; oligodendrocytes; remyelination; smoothened agonists.

Figure 1

The role of Shh (Sonic Hedgehog) in neural stem cell (NSC) commitment to oligodendrocyte differentiation during remyelination. The process of oligodendrocyte maturation from NSCs to myelinating oligodendrocytes (mOL) requires Shh signaling reactivation. Smo activity seems to be crucial during the differentiation from premyelinating OLs (pre-OL) to immature oligodendrocytes (iOL). Smo agonists, such as Clobetasol (CLOB) or cholesterol, stimulate this passage while Smo inhibitors, such as cyclopamine (CYP) or itraconazole (ITRA), impair OL maturation via a poorly understood process.