| Autor: |
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 |
| Zdroj: |
Nature Neuroscience; November 2024, Vol. 27 Issue: 11 p2073-2085, 13p |
| Abstrakt: |
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. Dorablation 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 Dorconditional 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. |
| Databáze: |
Supplemental Index |
| Externí odkaz: |
|
Full text from SpringerLink