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

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.少突胶质细胞（oligodendrocyte, OL）的髓鞘形成潜能受损，而非少突胶质前体细胞的分化能力缺失，与多发性硬化等脱髓鞘疾病的髓鞘再生失败密切相关。然而，髓鞘形成以及髓鞘再生随年龄衰退的具体机制仍不明晰。本研究鉴定出一种在成熟少突胶质细胞中具有活性的转录调控因子Dor，其为中枢神经系统（central nervous system, CNS）髓鞘形成与髓鞘再生的关键调控介质。基因组占据分析与转录组分析显示，Dor可与Sox10相互作用，并靶向调控髓鞘形成的基因增强子，其中包括新发现的、对少突胶质细胞成熟至关重要的少突胶质细胞富集型核因子Prr18。代谢组学分析显示，Dor对于α-酮戊二酸（alpha-ketoglutarate, α-KG）的生成与脂质生物合成至关重要。补充α-KG可增强脂质生物合成，修复Dor突变小鼠的少突胶质细胞成熟缺陷，同时逆转衰老小鼠中随年龄增长的髓鞘再生效率下降以及记忆障碍。综上，本研究发现将成熟少突胶质细胞中具有活性的Dor调控活性与α-KG介导的脂质代谢相联系，从而促进髓鞘生成与髓鞘再生。