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.

The Current Challenges for Drug Discovery in CNS Remyelination

“…These NSCs are committed to the oligodendrocyte (OL) lineage. They differentiate into OPCs under the control of mitogenic growth factors, such as epidermal growth factor (EGF), fibroblast growth factor (FGF), and plated-derived growth factor (PDGF), and morphogenetic factors such as Sonic Hedgehog (Shh) [ 17 , 78 , 79 , 80 ]. EGF expression can influence cortical progenitor fate choice during the neural progenitor cell (NPC) proliferative stage [ 81 , 82 ].…”

“…Smo is a G protein-coupled receptor (GPCR) consisting of seven transmembrane domains, belonging to the Frizzled family, that responds to an increase in Shh. In the canonical Smo activation pathway, the interaction of the Shh ligand with PTCH results in Smo migration to the cilium, a process that leads to a chain of events that culminates in a change in the balance of activating and repressor forms of Gli factors (GLI1, 2, and 3) [ 78 , 92 ]. GLI proteins can activate or repress gene transcription, regulating cell differentiation and proliferation [ 92 ].…”

“…However, during NPC commitment to OPCs, Gli1 is repressed upon Shh/Smo activation [ 90 ]. Why and how, during remyelination, Shh/PITCH/Smo signaling results in Gli1 downregulation remains to be clarified [ 78 , 79 , 90 ]. The role of Smo activation during OPC differentiation until OL maturation remains to be determined.…”

“…The role of Smo activation during OPC differentiation until OL maturation remains to be determined. The idea that Smo activation is required also during OPC differentiation to mature OLs is suggested by the identification of several anti-inflammatory drugs with Smo agonist activity in phenotypical screens for remyelination agents [ 7 , 33 , 78 ] ( Table 2 ).…”

EGFR/ErbB Inhibition Promotes OPC Maturation up to Axon Engagement by Co-Regulating PIP2 and MBP

“…Canonical Shh signaling leads to the activation of the G-protein-coupled seven-pass transmembrane receptor Smoothened (Smo) that binds to the transcription factors Gli1-3, thus promoting Shh-mediated gene transcription. For unclear reason, Shh upregulation does not result in Gli1 upregulation after remyelination stimuli, with the consequence that NPCs are fated to the OPC lineage [10,12,13,14,15,16,17]. The expression of myelin regulatory factor (Myrf) marks the entrance of OPCs into the second phase of differentiation.…”