Center for Translational Medicine, Key Laboratory of Birth Defects and Related Disease of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu, China.
Department of Pediatrics, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Nat Neurosci. 2024 Nov;27(11):2073-2085. doi: 10.1038/s41593-024-01754-9. Epub 2024 Sep 12.
The decreased ability of mature oligodendrocytes to produce myelin negatively affects remyelination in demyelinating diseases and aging, but the underlying mechanisms are incompletely understood. In the present study, we identify a mature oligodendrocyte-enriched transcriptional coregulator diabetes- and obesity-related gene (DOR)/tumor protein p53-inducible nuclear protein 2 (TP53INP2), downregulated in demyelinated lesions of donors with multiple sclerosis and in aged oligodendrocyte-lineage cells. Dor ablation in mice of both sexes results in defective myelinogenesis and remyelination. Genomic occupancy in oligodendrocytes and transcriptome profiling of the optic nerves of wild-type and Dor conditional knockout mice reveal that DOR and SOX10 co-occupy enhancers of critical myelinogenesis-associated genes including Prr18, encoding an oligodendrocyte-enriched, proline-rich factor. We show that DOR targets regulatory elements of genes responsible for α-ketoglutarate biosynthesis in mature oligodendrocytes and is essential for α-ketoglutarate production and lipid biosynthesis. Supplementation with α-ketoglutarate restores oligodendrocyte-maturation defects in Dor-deficient adult mice and improves remyelination after lysolecithin-induced demyelination and cognitive function in 17-month-old wild-type mice. Our data suggest that activation of α-ketoglutarate metabolism in mature oligodendrocytes can promote myelin production during demyelination and aging.
成熟少突胶质细胞产生髓鞘的能力下降会对脱髓鞘疾病和衰老中的髓鞘再生产生负面影响，但其中的机制尚不完全清楚。在本研究中，我们鉴定了一种丰富表达于成熟少突胶质细胞的转录共调控因子——糖尿病和肥胖相关基因（DOR）/肿瘤蛋白 p53 诱导核蛋白 2（TP53INP2），该基因在多发性硬化症患者的脱髓鞘病变和衰老的少突胶质细胞谱系细胞中下调。雌雄小鼠的 Dor 缺失导致髓鞘生成和髓鞘再生缺陷。野生型和 Dor 条件性敲除小鼠视神经的基因组结合和转录组分析显示，DOR 和 SOX10 共同占据关键髓鞘生成相关基因的增强子，包括编码富含脯氨酸的少突胶质细胞特异性因子 Prr18 的基因。我们表明，DOR 靶向成熟少突胶质细胞中负责 α-酮戊二酸生物合成的基因的调控元件，对于 α-酮戊二酸的产生和脂质生物合成是必需的。补充 α-酮戊二酸可恢复 Dor 缺陷型成年小鼠的少突胶质细胞成熟缺陷，并改善卵磷脂诱导的脱髓鞘后的髓鞘再生和 17 月龄野生型小鼠的认知功能。我们的数据表明，激活成熟少突胶质细胞中的 α-酮戊二酸代谢可以促进脱髓鞘和衰老过程中的髓鞘生成。
