Mechanisms of myelin membrane biogenesis in the central nervous system
Final Report Abstract
Rapid conduction of nerve impulses requires coating of axons by myelin. To function as an electrical insulator, myelin is generated as a tightly-packed, lipid-rich multilayered membrane sheath. Knowledge about the mechanisms that govern myelin membrane biogenesis is required to understand myelin disassembly as it occurs in diseases such as multiple sclerosis. We show that myelin basic protein drives myelin biogenesis using weak forces arising from its inherent capacity to phase separate. The association of myelin basic protein molecules to the inner leaflet of the membrane bilayer induces a phase transition into a cohesive mesh-like protein network. The formation of this protein network shares features with amyloid fibril formation. The process is driven by phenylalanine-mediated hydrophobic and amyloid-like interactions that provide the molecular basis for protein extrusion and myelin membrane zippering. These findings uncover a physicochemical mechanism of how a cytosolic protein regulates the morphology of a complex membrane architecture. These results provide a key mechanism in myelin membrane biogenesis with implications for disabling demyelinating diseases of the central nervous system.
Publications
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(2013) A global in vivo Drosophila RNAi screen identifies a key role of ceramide phosphoethanolamine for glial ensheathment of axons. PloS Genetics, Dec;9(12):e1003980
Ghosh A, Kling T, Snaidero N, Sampaio JL, Shevchenko A, Schulz JB, Voigt A, Simons M
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(2013). Loss of electrostatic cell-surface repulsion mediates myelin membrane adhesion and compaction in the central nervous system. Proc Natl Acad Sci USA Feb 19;110(8):3143-8
M. Bakhti, N. Snaidero, D. Schneider , S. Aggarwal , W. Möbius, A. Janshoff, M. Eckhardt, K.A. Nave, M. Simons
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(2013). Myelin Membrane Assembly Is Driven by a Phase Transition of Myelin Basic Proteins Into a Cohesive Protein Meshwork. PLoS Biology Jun;11(6):e1001577
Aggarwal S, Snaidero N, Pähler G, Frey S, Sànchez S, Zweckstetter M, Janshoff A, Weil MT, Schaap IA, Görlich D, Simons M
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(2014) Myelin membrane wrapping of CNS axons by PI(3,4,5)P3-dependent polarized growth at the inner tongue. Cell Jan 16;156(1-2):277-90
Snaidero N, Möbius W, Czopka T, Hekking L.H.P., Mathisen C, Verkleij D, Goebbels S, Edgar J, Merkler D, Lyons D.A., Nave K.A., Simons M.
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(2015) Actin filament turnover drives leading edge growth during myelin sheath formation in the central nervous system. Developmental Cell 27:139-51
Nawaz S, Sánchez P, Schmitt S, Snaidero N, Mitkovski M, Velte C, Brückner BR, Alexopoulos I, Czopka T, Jung SY, Rhee JS, Janshoff A, Witke W, Schaap IA, Lyons DA, Simons M
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(2016) Reorganization of Lipid Diffusion by Myelin Basic Protein as Revealed by STED Nanoscopy. Biophys J. Jun 7;110(11):2441-50
Steshenko O, Andrade DM, Honigmann A, Mueller V, Schneider F, Sezgin E, Hell SW, Simons M, Eggeling C
