Pathological myelin outfoldings: cellular cause and behavioral consequences
Final Report Abstract
Myelin serves as an insulator of neuronal axons that facilitates rapid and precise impulse propagation in the nervous system, a prerequisite for normal motor, sensory, and cognitive capabilities. By transmission electron microscopy, a healthy myelin sheath comprises compacted membrane layers spiraling around the cross-sectioned axon. The axon/myelin-unit becomes impaired in myelin-related disorders and upon normal aging. However, the molecular causes and functional consequences of many pathological features have remained unknown, including the frequently observed myelin outfoldings. In this project we have systematically compared both the neuropathology and the myelin proteome in the central nervous system of three mouse models of myelin disease (spastic paraplegia, hypomyelinating leukodystrophy). We found that all three models have in common that they display myelin outfoldings and a strong reduction of a previously unrecognized structure, myelin septin filaments. By light and electron microscopy, myelin septin filaments localize to the innermost non-compacted myelin layer, in which they extend longitudinally along myelinated axons. Genetic disruption of these filaments in Septin8-mutant mice causes myelin outfoldings as a highly specific neuropathology. The assembly of septin filaments as one of the latest steps of myelin maturation in the central nervous system is thus required to scaffold the axon/myelin-unit. We also find that expression of the cytoskeletal adaptor protein anillin (ANLN) in myelin-forming oligodendrocytes is required for myelin septin assembly, its deficiency thus causes the emergence of myelin outfoldings. When evaluating the functional consequences of myelin outfoldings in Septin8- and Anln-mutant mice we find a reduction of nerve conduction velocity by over 15%, as measured in the spinal cord. Since myelin outfoldings are a poorly understood hallmark of myelin disease and brain aging we assessed axon/myelin-units in various myelin mutant mice by focused ion beam-scanning electron microscopy (FIB-SEM); by three-dimensional reconstruction and morphometric analyses, myelin outfoldings are large sheets of multiple compact membrane layers that extend up to 15 μm longitudinally along axons. Together, this project has discovered that anillin-dependent assembly of septin filaments is required for the normal scaffolding of mature myelin sheaths, facilitating rapid nerve conduction in the healthy CNS.
Publications
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Septins in the glial cells of the nervous system. Biological Chemistry, 395(2), 143-149.
Patzig, Julia; Dworschak, Michelle S.; Martens, Ann-Kristin & Werner, Hauke B.
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Septin/anillin filaments scaffold central nervous system myelin to accelerate nerve conduction. eLife, 5(2016, 8, 9).
Patzig, Julia; Erwig, Michelle S; Tenzer, Stefan; Kusch, Kathrin; Dibaj, Payam; Möbius, Wiebke; Goebbels, Sandra; Schaeren-Wiemers, Nicole; Nave, Klaus-Armin & Werner, Hauke B
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Anillin facilitates septin assembly to prevent pathological outfoldings of central nervous system myelin. eLife, 8(2019, 1, 23).
Erwig, Michelle S; Patzig, Julia; Steyer, Anna M; Dibaj, Payam; Heilmann, Mareike; Heilmann, Ingo; Jung, Ramona B; Kusch, Kathrin; Möbius, Wiebke; Jahn, Olaf; Nave, Klaus-Armin & Werner, Hauke B
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Focused ion beam‐scanning electron microscopy links pathological myelin outfoldings to axonal changes in mice lacking Plp1 or Mag. Glia, 71(3), 509-523.
Steyer, Anna M.; Buscham, Tobias J.; Lorenz, Charlotta; Hümmert, Sophie; Eichel‐Vogel, Maria A.; Schadt, Leonie C.; Edgar, Julia M.; Köster, Sarah; Möbius, Wiebke; Nave, Klaus‐Armin & Werner, Hauke B.
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Targeted inactivation of the Septin2 and Septin9 genes in myelinating Schwann cells of mice. Cytoskeleton, 80(7-8), 290-302.
Martens, Ann‐Kristin; Erwig, Michelle; Patzig, Julia; Fledrich, Robert; Füchtbauer, Ernst‐Martin & Werner, Hauke B.
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Focused ion beam-scanning electron microscopy links pathological myelin outfoldings to axonal changes in mice lacking Plp1 or Mag. Glia 71:509. The datasets for this publication: Electron Microscopic Image Archive (EMPIAR); accession numbers EMPIAR-11214, EMPIAR-11215, EMPIAR-11216, EMPIAR-11219, EMPIAR-11220, EMPIAR-11237, EMPIAR-11238, EMPIAR- 11239 and EMPIAR-11240.
Steyer, Anna M.; Buscham, Tobias J.; Lorenz, Charlotta; Hümmert, Sophie; Eichel‐Vogel, Maria A.; Schadt, Leonie C.; Edgar, Julia M.; Köster, Sarah; Möbius, Wiebke; Nave, Klaus‐Armin & Werner, Hauke B.
