Transforming growth factor-β receptor I kinase plays a crucial role in oligodendrocyte regeneration after demyelination

Abstract

Multiple sclerosis (MS) is an autoimmune disease characterized by the loss of oligodendrocytes (OLs) and axon demyelination in the central nervous system. Most therapeutic agents focus on regulating the immune response by suppressing autoimmune reactions. Therefore, developing therapeutic agents that promote remyelination by OLs at disease sites that have already undergone demyelination is necessary. In this study, we generated a new transgenic zebrafish with high efficiency for OL ablation and established a high-throughput screening (HTS)-based platform to identify therapeutic candidates that promote remyelination. Next, we screened a library of kinase inhibitors and identified one candidate, a transforming growth factor-β receptor I (TGF-βRI) kinase inhibitor. Treatment with this kinase inhibitor rapidly recruited microglia to induce clearance of myelin debris, early after OL removal. It also increased the proliferation of OL progenitor cells in demyelinating zebrafish larvae, resulting in restored OL numbers and reduced locomotor activity. Based on these results, we expect our HTS-based platform, along with our newly developed zebrafish model, to be very useful for identifying therapeutic agents that promote remyelination. Furthermore, since the candidate TGF-βRI kinase inhibitor identified in this study restored the phenotype following demyelination, we suggest that TGF-βRI kinase may potentially be a therapeutic target for the treatment of demyelinating diseases.