5-Fluorouracil causes severe CNS demyelination by disruption of TCF7L2/HDAC1/HDAC2 complex in adolescent mice

•Systemic administration with 5-FU could induce acute demyelination in the central nervous system of adolescent mice.•5-FU-caused demyelination was attributed to the death of OPCs.•5-FU-decreased TCF7L2 expression results in disassociating with HDAC1/2 to damage OLs myelination.

Several studies have showed the anti-cancer efficacy of 5-FU (5-fluorouracil) on pediatric tumors. Although the delayed demyelination induced by 5-FU in adult patients has been reported, the effect of 5-FU on oligodendrocyte myelination in adolescence is still unknown. Here, we demonstrate that systemic administration with 5-FU leads to immediate demyelination in the central nervous system (CNS) of adolescent mice, which is mainly attributed to the death of OLs. Gene-chip microarray transcriptome analysis identifies that oligodendrocyte-specific factor TCF7L2 may be a toxic target of 5-FU-impaired myelination. 5-FU-decreased TCF7L2 results in disruption of the interaction between TCF7L2 and HDAC1/2. Inhibition of crucial myelination-promoting factors by 5-FU is more significantly antagonized by co-transfection of TCF7L2, HDAC1 and HDAC2 than TCF7L2 alone. Our findings reveal that 5-FU could acutely induce the severe myelin degeneration in adolescence and disruption of TCF7L2/HDAC1/HDAC2 complex is at least partially involved in 5-FU-induced demyelination.

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