Mature myelin maintenance requires Qki to coactivate PPARβ-RXRα–mediated lipid metabolism
Xin Zhou, Chenxi He, Jiangong Ren, Congxin Dai, Sharon R. Stevens, Qianghu Wang, Daniel Zamler, Takashi Shingu, Liang Yuan, Chythra R. Chandregowda, Yunfei Wang, Visweswaran Ravikumar, Arvind U.K. Rao, Feng Zhou, Hongwu Zheng, Matthew N. Rasband, Yiwen Chen, Fei Lan, Amy B. Heimberger, Benjamin M. Segal, Jian Hu
Xin Zhou, Chenxi He, Jiangong Ren, Congxin Dai, Sharon R. Stevens, Qianghu Wang, Daniel Zamler, Takashi Shingu, Liang Yuan, Chythra R. Chandregowda, Yunfei Wang, Visweswaran Ravikumar, Arvind U.K. Rao, Feng Zhou, Hongwu Zheng, Matthew N. Rasband, Yiwen Chen, Fei Lan, Amy B. Heimberger, Benjamin M. Segal, Jian Hu
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Research Article Metabolism Neuroscience

Mature myelin maintenance requires Qki to coactivate PPARβ-RXRα–mediated lipid metabolism

Abstract

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.

Authors

Xin Zhou, Chenxi He, Jiangong Ren, Congxin Dai, Sharon R. Stevens, Qianghu Wang, Daniel Zamler, Takashi Shingu, Liang Yuan, Chythra R. Chandregowda, Yunfei Wang, Visweswaran Ravikumar, Arvind U.K. Rao, Feng Zhou, Hongwu Zheng, Matthew N. Rasband, Yiwen Chen, Fei Lan, Amy B. Heimberger, Benjamin M. Segal, Jian Hu

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Figure 4

Qki controls fatty acid desaturation and elongation and HFD alleviates Qki deficiency–induced demyelination.

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Qki controls fatty acid desaturation and elongation and HFD alleviates Q...
(A and B) Quantification of the concentration of total and each species of fatty acids (FAs) in the spinal cords of Qk-iCKO mice and controls 5 weeks post injection (wpi) (n = 5 mice/group). (C) Heatmap plotting the compositions of each fatty acid species in the samples in A (n = 5 mice/group). The green boxes highlight the saturated and monounsaturated LCFAs and VLCFAs. (D) Quantification of the MUFA/SFA ratios in the samples in A (n = 5 mice/group). (E) Schema showing the desaturating and elongating reactions of fatty acids with the reduction in specific fatty acid molecules (from lipidomic data) and the downregulated corresponding enzymes (from RNA-seq data) in Qk-iCKO mice relative to controls. (F) Quantification of the product/substrate ratios of representative fatty acid desaturating and elongating reactions in the samples in A (n = 5 mice/group). (G and H) The clinical scores (G) and Kaplan-Meier overall survival curves (log-rank test; H) of Qk-iCKO mice and controls fed a normal diet (ND) or HFD. The experimental mouse number is indicated in G. (I) Latency to fall (in seconds) off the rotarod (5 rpm) for Qk-iCKO mice and controls fed an ND or HFD for 5 wpi. (J) Representative electron micrographs and quantification of the percentage of myelinated axons and g-ratio of the optic nerves of Qk-iCKO mice and controls fed an ND or HFD for 5 wpi. Scale bars: 500 nm. (K) Representative images and quantification of FluoroMyelin level in the corpus callosum of Qk-iCKO mice and controls fed an ND or HFD for 5 wpi. Scale bars: 50 μm. Data are mean ± SD. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001 by Student’s t test (A, B, D, and F) or 1-way ANOVA followed by Bonferroni’s post hoc test (G and I–K). NS, not significant.