Mature myelin maintenance requires Qki to coactivate PPARβ-RXRα-mediated lipid metabolism.
In: The Journal of clinical investigation, Jg. 130 (2020-05-01), Heft 5, S. 2220-2236
Online
academicJournal
Zugriff:
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 PPARβ-RXRα complex, which controls the transcription of lipid-metabolism genes, particularly those involved in fatty acid desaturation and elongation. Treatment of Qki-depleted mice with PPARβ/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.
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Mature myelin maintenance requires Qki to coactivate PPARβ-RXRα-mediated lipid metabolism.
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Autor/in / Beteiligte Person: | Zhou, X ; He, C ; Ren, J ; Dai, C ; Stevens, SR ; Wang, Q ; Zamler, D ; Shingu, T ; Yuan, L ; Chandregowda, CR ; Wang, Y ; Ravikumar, V ; Rao, AU ; Zhou, F ; Zheng, H ; Rasband, MN ; Chen, Y ; Lan, F ; Heimberger, AB ; Segal, BM ; Hu, J |
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Zeitschrift: | The Journal of clinical investigation, Jg. 130 (2020-05-01), Heft 5, S. 2220-2236 |
Veröffentlichung: | 1999- : Ann Arbor, MI : American Society for Clinical Investigation ; <i>Original Publication</i>: New Haven [etc.] American Society for Clinical Investigation., 2020 |
Medientyp: | academicJournal |
ISSN: | 1558-8238 (electronic) |
DOI: | 10.1172/JCI131800 |
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