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 2

Loss of Qki interrupts mature myelin lipid homeostasis.

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Loss of Qki interrupts mature myelin lipid homeostasis. (A–C) Representa...
(A–C) Representative images and quantification of PLP (A), MBP (B), and MAG (C) in the corpus callosum of Qk-iCKO mice and controls 1, 2, and 5 weeks post injection (wpi) (n = 4 mice/group). Scale bars: 50 μm. (D and E) Quantification of staining of PLP, MBP, MAG, and FluoroMyelin in the optic nerves (D) and spinal cords (E) of Qk-iCKO mice and controls 5 wpi (n = 4 mice/group). Fl, FluoroMyelin. (F) Immunoblots and quantification showing the expression of PLP, MBP, and myelin oligodendrocyte glycoprotein (MOG) of Qk-iCKO mice and controls 2 and 5 wpi (n = 3 mice/group). (G) Representative images and quantification of staining of FluoroMyelin in the corpus callosum of Qk-iCKO mice and controls 1, 2, and 5 wpi (n = 4 mice/group). Scale bars: 50 μm. (H) Schema depicting the workflow for lipidomic analyses. (I) Quantification of the concentration (μmol/g tissue) of the total lipids measured by mass spectrometry in the spinal cords of Qk-iCKO mice and controls 5 wpi (n = 5 mice/group). (J) Volcano plot (top) illustrating the alterations in the concentrations of each lipid molecule in the samples in I (n = 5 mice/group). The dotted line represents P = 0.05. Pie graph (bottom) illustrating the numbers and percentages of significantly decreased, increased, and unchanged molecules in Qk-iCKO mice relative to controls. (K) Quantification of the concentrations of lipid subclasses in the samples in I (n = 5 mice/group). PC, phosphatidylcholine; PE, phosphatidylethanolamine; PI, phosphatidylinositol; LPC, lysophosphatidylcholine; LPE, lysophosphatidylethanolamine; SM, sphingomyelin; CER, ceramide; HCER, hexosylceramide; LCER, lactosylceramide; DCER, dihydroceramide. Data are mean ± SD. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001 by 2-way ANOVA with Holm-Sidak multiple-comparisons test (A–C and G) or Student’s t test (D–F, I, and K). NS, not significant.