Antagonistic Functions of MBP and CNP Establish Cytosolic Channels in CNS Myelin
Nicolas Snaidero,
Caroline Velte,
Matti Myllykoski,
Arne Raasakka,
Alexander Ignatev,
Hauke B. Werner,
Michelle S. Erwig,
Wiebke Möbius,
Petri Kursula,
Klaus-Armin Nave,
Mikael Simons
Affiliations
Nicolas Snaidero
Cellular Neuroscience, Max Planck Institute of Experimental Medicine, 37075 Göttingen, Germany; Institute of Neuronal Cell Biology, Technical University Munich, 80805 Munich, Germany
Caroline Velte
Cellular Neuroscience, Max Planck Institute of Experimental Medicine, 37075 Göttingen, Germany
Matti Myllykoski
Faculty of Biochemistry and Molecular Biology and Biocenter Oulu, University of Oulu, 90014 Oulu, Finland
Arne Raasakka
Faculty of Biochemistry and Molecular Biology and Biocenter Oulu, University of Oulu, 90014 Oulu, Finland; Department of Biomedicine, University of Bergen, 5009 Bergen, Norway
Alexander Ignatev
Faculty of Biochemistry and Molecular Biology and Biocenter Oulu, University of Oulu, 90014 Oulu, Finland
Hauke B. Werner
Department of Neurogenetics, Max Planck Institute of Experimental Medicine, 37075 Göttingen, Germany
Michelle S. Erwig
Department of Neurogenetics, Max Planck Institute of Experimental Medicine, 37075 Göttingen, Germany
Wiebke Möbius
Department of Neurogenetics, Max Planck Institute of Experimental Medicine, 37075 Göttingen, Germany; Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), 37075 Göttingen, Germany
Petri Kursula
Faculty of Biochemistry and Molecular Biology and Biocenter Oulu, University of Oulu, 90014 Oulu, Finland; Department of Biomedicine, University of Bergen, 5009 Bergen, Norway
Klaus-Armin Nave
Department of Neurogenetics, Max Planck Institute of Experimental Medicine, 37075 Göttingen, Germany; Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), 37075 Göttingen, Germany
Mikael Simons
Cellular Neuroscience, Max Planck Institute of Experimental Medicine, 37075 Göttingen, Germany; Institute of Neuronal Cell Biology, Technical University Munich, 80805 Munich, Germany; German Center for Neurodegenerative Disease (DZNE), 6250 Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), 81377 Munich, Germany; Corresponding author
Summary: The myelin sheath is a multilamellar plasma membrane extension of highly specialized glial cells laid down in regularly spaced segments along axons. Recent studies indicate that myelin is metabolically active and capable of communicating with the underlying axon. To be functionally connected to the neuron, oligodendrocytes maintain non-compacted myelin as cytoplasmic nanochannels. Here, we used high-pressure freezing for electron microscopy to study these cytoplasmic regions within myelin close to their native state. We identified 2,′3′-cyclic nucleotide 3′-phosphodiesterase (CNP), an oligodendrocyte-specific protein previously implicated in the maintenance of axonal integrity, as an essential factor in generating and maintaining cytoplasm within the myelin compartment. We provide evidence that CNP directly associates with and organizes the actin cytoskeleton, thereby providing an intracellular strut that counteracts membrane compaction by myelin basic protein (MBP). Our study provides a molecular and structural framework for understanding how myelin maintains its cytoplasm to function as an active axon-glial unit. : Snaidero et al. provide evidence that a system of cytoplasmic-rich channels is generated in myelin sheaths by the antagonist function of MBP and CNP. The authors suggest that these channels are required to provide trophic support to neurons and maintain functional axon-glial units over a long period of time. Keywords: myelin, oligodendrocytes, glia, axons, neurodegeneration, CNP, MBP, demyelinating diseases