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Wu, J.* ; Kislinger, G.* ; Duschek, J.* ; Durmaz, A.D.* ; Wefers, B.* ; Feng, R.* ; Nalbach, K.* ; Wurst, W. ; Behrends, C.* ; Schifferer, M.* ; Simons, M.*

Nonvesicular lipid transfer drives myelin growth in the central nervous system.

Nat. Commun. 15:9756 (2024)

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Oligodendrocytes extend numerous cellular processes that wrap multiple times around axons to generate lipid-rich myelin sheaths. Myelin biogenesis requires an enormously productive biosynthetic machinery for generating and delivering these large amounts of newly synthesized lipids. Yet, a complete understanding of this process remains elusive. Utilizing volume electron microscopy, we demonstrate that the oligodendroglial endoplasmic reticulum (ER) is enriched in developing myelin, extending into and making contact with the innermost myelin layer where growth occurs. We explore the possibility of transfer of lipids from the ER to myelin, and find that the glycolipid transfer protein (GLTP), implicated in nonvesicular lipid transport, is highly enriched in the growing myelin sheath. Mice with a specific knockout of Gltp in oligodendrocytes exhibit ER pathology, hypomyelination and a decrease in myelin glycolipid content. In summary, our results demonstrate a role for nonvesicular lipid transport in CNS myelin growth, revealing a cellular pathway in developmental myelination.

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