TY - JOUR
T1 - Mature myelin maintenance requires Qki to coactivate PPARβ-RXRα-mediated lipid metabolism
AU - Zhou, Xin
AU - He, Chenxi
AU - Ren, Jiangong
AU - Dai, Congxin
AU - Stevens, Sharon R.
AU - Wang, Qianghu
AU - Zamler, Daniel
AU - Shingu, Takashi
AU - Yuan, Liang
AU - Chandregowda, Chythra R.
AU - Wang, Yunfei
AU - Ravikumar, Visweswaran
AU - Rao, Arvind U.K.
AU - Zhou, Feng
AU - Zheng, Hongwu
AU - Rasband, Matthew N.
AU - Chen, Yiwen
AU - Lan, Fei
AU - Heimberger, Amy B.
AU - Segal, Benjamin M.
AU - Hu, Jian
N1 - Publisher Copyright:
© 2020, American Society for Clinical Investigation.
PY - 2020/5/1
Y1 - 2020/5/1
N2 - 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.
AB - 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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U2 - 10.1172/JCI131800
DO - 10.1172/JCI131800
M3 - Article
C2 - 32202512
AN - SCOPUS:85084118406
SN - 0021-9738
VL - 130
SP - 2220
EP - 2236
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 5
ER -