Mature myelin maintenance requires Qki to coactivate PPARβ-RXRα-mediated lipid metabolism. Academic Article uri icon

Overview

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.

publication date

  • May 1, 2020

Research

keywords

  • DNA-Binding Proteins
  • Demyelinating Diseases
  • Lipid Metabolism
  • Myelin Sheath
  • PPAR-beta
  • RNA-Binding Proteins

Identity

PubMed Central ID

  • PMC7191000

Scopus Document Identifier

  • 85084118406

Digital Object Identifier (DOI)

  • 10.1073/pnas.0506580102

PubMed ID

  • 32202512

Additional Document Info

volume

  • 130

issue

  • 5