| First Author | Huang G | Year | 2024 |
| Journal | Nat Neurosci | Volume | 27 |
| Issue | 11 | Pages | 2073-2085 |
| PubMed ID | 39266660 | Mgi Jnum | J:359651 |
| Mgi Id | MGI:7781925 | Doi | 10.1038/s41593-024-01754-9 |
| Citation | Huang G, et al. (2024) DOR activation in mature oligodendrocytes regulates alpha-ketoglutarate metabolism leading to enhanced remyelination in aged mice. Nat Neurosci 27(11):2073-2085 |
| abstractText | 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 alpha-ketoglutarate biosynthesis in mature oligodendrocytes and is essential for alpha-ketoglutarate production and lipid biosynthesis. Supplementation with alpha-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 alpha-ketoglutarate metabolism in mature oligodendrocytes can promote myelin production during demyelination and aging. |
