Dor regulates alpha-KG metabolic pathways in mature oligodendrocytes to enhance myelination and reverse age-related remyelination decline [RNA-seq]

Impairment of oligodendrocyte (OL) myelinogenic potential, rather than inability of oligodendrocyte precursors to differentiate, is implicated in remyelination failure in demyelinating diseases such as multiple sclerosis. However, the mechanisms underlying myelinogenesis and age-related decline in remyelination remain elusive. Here, we identify a mature-OL-active transcriptional regulator Dor as a critical mediator of CNS myelination and remyelination. Genomic occupancy and transcriptomic analyses revealed that Dor interacts with Sox10 and targets the enhancers of myelinogenesis-regulatory genes including a newly identified OL-enriched nuclear factor Prr18 required for OL maturation. Metabolomic profiling showed that Dor is critical for alpha-ketoglutarate (alpha-KG) production and lipid biosynthesis. Supplementation with alpha-KG enhanced lipid biosynthesis and restored OL maturation defects in Dor-mutant mice while reversing the age-associated decline in remyelination efficiency and memory deficits in aging mice. Thus, our findings connect the OL-active Dor regulatory activity to alpha-KG-mediated lipid metabolism in mature OLs to thereby facilitate myelin production and remyelination.