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

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

Publication date: Mar 23, 2020

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 PPAR?-RXR? complex, which controls the transcription of lipid-metabolism genes, particularly those involved in fatty acid desaturation and elongation. Treatment of Qki-depleted mice with PPAR?/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.

Concepts Keywords
Axon Rapid demyelination
Coactivator Branches of biology
Demyelinating Diseases Glial cells
Demyelination Organ systems
Disability Nervous system
Electrically Insulating Myelin
Fat Oligodendrocyte
Fatty Acid QKI
Fatty Acids Demyelinating disease
Homeostasis Lipid metabolism
Lipid Axon
Lipid Metabolism Neuroscience
Lipid Synthesis
Lipids
Mice
Monounsaturated Fatty Acids
Multiple Sclerosis
Myelin
Neurological
Oligodendrocyte
Oligodendrocytes
Phenotypes
PPAR
Progressive
RXR
Transcription

Semantics

Type Source Name
disease MESH demyelination
disease MESH primary progressive multiple sclerosis
disease MESH Multiple sclerosis

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