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RNA-seq profiles of WT and Qk-KO freshly isolated oligodendrocytes

ABSTRACT: Lipid-rich myelin forms insulating axon-wrapping multilayers essential for neural function, but how mature myelin maintains its structural lipid components remains obscure. Here we identify Quaking (Qki) as a major regulator of myelin lipid homeostasis. Qki depletion in adult myelinating oligodendrocytes disrupted myelin lipid metabolism and caused demyelination, resulting in progressive neurological deficits that could be partially rescued by high-fat diet. Mechanistically, Qki serves as a coactivator of the PPARb-RXRa complex, which controls transcription of lipid-metabolism genes, particularly those for fatty acid desaturation and elongation. Treatment of Qki-depleted mice with PPARb or RXR agonists alleviated neurological disability and significantly extended mouse survival. Furthermore, a subset of lesions from patients with primary progressive multiple sclerosis were characterized by preferential reduction of myelin lipids and activities of lipid-metabolism pathways. Together, our findings demonstrate that continuous lipid synthesis is indispensable for mature myelin maintenance and highlight an underappreciated role of lipid metabolism in demyelinating diseases.

ORGANISM(S): Mus musculus

PROVIDER: GSE125581 | GEO | 2020/01/04

REPOSITORIES: GEO

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