四川大学贺雪莲团队近期取得重要工作进展，他们研究提出，成熟少突胶质细胞中DOR的激活通过调节α-酮戊二酸代谢来增强老年小鼠髓鞘再生能力。相关研究成果2024年9月12日在线发表于《自然—神经科学》杂志上。

据介绍，成熟少突胶质细胞产生髓鞘的能力降低会对脱髓鞘疾病和衰老的髓鞘再生产生负面影响，但其潜在机制尚不完全清楚。

研究人员鉴定了一种成熟的富含少突胶质细胞的，转录共调节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），在多发性硬化症供体的脱髓鞘病变和老年少突胶质细胞谱系细胞中下调。对雌雄小鼠进行Dor消融会导致髓鞘形成和髓鞘再生缺陷。

少突胶质细胞中的基因组占有率，和野生型和Dor条件敲除小鼠视神经的转录组分析表明，Dor和SOX10共同占据了关键髓鞘形成相关基因的增强子，包括编码富含少突胶质、富含脯氨酸因子的Prr18。研究人员发现，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调控元件，对α-酮戊二酸的产生和脂质生物合成至关重要。补充α-酮戊二酸可恢复Dor缺陷成年小鼠的少突胶质细胞成熟缺陷，并改善17月龄野生型小鼠溶卵磷脂诱导脱髓鞘后的再髓鞘形成和认知功能。

总之，这一研究表明，成熟少突胶质细胞中α-酮戊二酸代谢的激活，可以促进脱髓鞘和衰老过程中髓鞘的产生。

附：英文原文

Title: DOR activation in mature oligodendrocytes regulates α-ketoglutarate metabolism leading to enhanced remyelination in aged mice

Author: Huang, Guojiao, Li, Zhidan, Liu, Xuezhao, Guan, Menglong, Zhou, Songlin, Zhong, Xiaowen, Zheng, Tao, Xin, Dazhuan, Gu, Xiaosong, Mu, Dezhi, Guo, Yingkun, Zhang, Lin, Zhang, Liguo, Lu, Q. Richard, He, Xuelian

Issue&Volume: 2024-09-12

Abstract: 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.

DOI: 10.1038/s41593-024-01754-9

Source: https://www.nature.com/articles/s41593-024-01754-9