MAZ regulates ferroptosis, apoptosis and differentiation of oligodendrocyte precursor cells

Abstract

Oligodendrocyte precursor cells (OPCs) respond rapidly to demyelination injury. However, the rescuing effects may be hindered by cell death of OPCs, leading to incomplete remyelination. This study aimed to explore the expression of MYC-associated zinc finger protein (MAZ) in demyelinated mice and the effects of MAZ on cell death form and differentiation of OPCs. Mice received demyelinating agent (cuprizone, CZ) for 5 weeks. Histological staining demonstrated that CZ feeding triggered demyelination in the corpus callosum (CC). Detection of iron content and ferroptosis markers indicated that ferroptosis was inducted in the CC of CZ-treated mice. Notably, we found CZ feeding resulted in a reduction of MAZ expression within the CC. Using CCK-8 assay, detection of iron content, MDA level, GSH level, and ferroptosis markers, lipid ROS detection, and immunofluorescence staining for 4-HNE, we found that knockdown of MAZ facilitated OPC ferroptosis. We also evaluated the susceptibility of MAZ-overexpressing OPCs to ferroptosis inducer, erastin, and demonstrated that MAZ-overexpressing OPCs were resistant to erastin-induced ferroptosis. TUNEL staining and western blot analysis indicated that MAZ knockdown promoted apoptosis of OPCs by inhibiting PI3K/Akt activation. Immunofluorescence staining of MBP indicated that knockdown of MAZ inhibited OPC differentiation. Moreover, we elucidate the mechanism responsible for MAZ’s protective effects on OPC death and differentiation, which may be achieved through transcriptional activation of SOX2. Our findings introduced MAZ as a beneficial modulator of OPC survival and differentiation, and it could serve as a potential therapeutic target for demyelination diseases.