Other
21 Authors
- He C,
- Zhou X,
- Yuan L,
- Zhou F,
- Rao AU,
- Chandregowda CR,
- Wang Q,
- Ravikumar V,
- Rasband MN,
- Hu J,
- Ren J,
- Stevens SR,
- Zamler D,
- Heimberger AB,
- Lan F,
- Dai C,
- Zheng H,
- Chen Y,
- Wang Y,
- Shingu T,
- Segal BM
| First Author | Zhou X | Year | 2020 |
| Journal | J Clin Invest | Volume | 130 |
| Issue | 5 | Pages | 2220-2236 |
| PubMed ID | 32202512 | Mgi Jnum | J:302268 |
| Mgi Id | MGI:6507980 | Doi | 10.1172/JCI131800 |
| Citation | Zhou X, et al. (2020) Mature myelin maintenance requires Qki to coactivate PPARbeta-RXRalpha-mediated lipid metabolism. J Clin Invest 130(5):2220-2236 |
| abstractText | Lipid-rich myelin forms electrically insulating, axon-wrapping multilayers that are essential for neural function, and mature myelin is traditionally considered metabolically inert. Surprisingly, we discovered that mature myelin lipids undergo rapid turnover, and quaking (Qki) is a major regulator of myelin lipid homeostasis. Oligodendrocyte-specific Qki depletion, without affecting oligodendrocyte survival, resulted in rapid demyelination, within 1 week, and gradually neurological deficits in adult mice. Myelin lipids, especially the monounsaturated fatty acids and very-long-chain fatty acids, were dramatically reduced by Qki depletion, whereas the major myelin proteins remained intact, and the demyelinating phenotypes of Qki-depleted mice were alleviated by a high-fat diet. Mechanistically, Qki serves as a coactivator of the PPARbeta-RXRalpha complex, which controls the transcription of lipid-metabolism genes, particularly those involved in fatty acid desaturation and elongation. Treatment of Qki-depleted mice with PPARbeta/RXR agonists significantly alleviated neurological disability and extended survival durations. Furthermore, a subset of lesions from patients with primary progressive multiple sclerosis were characterized by preferential reductions in myelin lipid contents, activities of various lipid metabolism pathways, and expression level of QKI-5 in human oligodendrocytes. Together, our results demonstrate that continuous lipid synthesis is indispensable for mature myelin maintenance and highlight an underappreciated role of lipid metabolism in demyelinating diseases. |
