BioProject

Lipid-rich myelin forms insulating axon-wrapping multilayers essential for neural function, but how mature myelin maintains its structural lipid components remains obscure. More...

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. Overall design: This study is to analyze the transcriptomic profiles of freshly isolated oligodendrocytes from Plp-CreERT2;QKLoxP/LoxP (Qk-KO) mice and control mice to determine the differentially expressed genes. Plp-CreERT2;QKLoxP/LoxP (Qk-KO) mice and control mice were injected with tamoxifen at 8-week, and brains were collected 4 days after tamoxifen injection to isolate oligodendrocyte freshly. The total RNAs were extracted by Rnasey kit and sent for sequencing with llumina HiSeq2000 Sequencer. Less...