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. Gene expression comparison between controls and Dor mutants of the optic nerves.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无法完成分化，被认为与多发性硬化等脱髓鞘疾病中的髓鞘再生失败密切相关。然而，髓鞘形成的分子机制以及随年龄增长出现的髓鞘再生能力下降的成因仍未阐明。本研究鉴定出一种在成熟少突胶质细胞中特异性活跃的转录调控因子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介导因子。基因组结合位点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相关基因的增强子，其中包括新鉴定出的、对少突胶质细胞成熟不可或缺的少突胶质细胞富集型核因子Prr18。代谢组谱分析表明，Dor对于α-酮戊二酸（alpha-ketoglutarate, α-KG）的生成与脂质生物合成过程至关重要。向Dor突变小鼠补充α-酮戊二酸，可增强其脂质生物合成过程，修复少突胶质细胞成熟缺陷，同时逆转衰老小鼠中随年龄增长出现的髓鞘再生效率下降与记忆功能障碍。综上，本研究将成熟少突胶质细胞中Dor介导的调控活性与α-酮戊二酸依赖的脂质代谢相联系，从而促进髓鞘生成与髓鞘再生。本研究包含对照组小鼠与视神经Dor突变小鼠之间的基因表达对比数据。