Myelin dysfunction/degradation in the central nervous system: why are myelin sheaths susceptible to damage?

  • Monika Bradl
Conference paper
Part of the 6th International Winter Conference on N eurodegeneration book series (NEURAL SUPPL, volume 55)


In the central nervous system, myelin sheaths are produced to electrically insulate axons and to increase the velocity of axonal conduction. They are highly complex structures, which are often destructed in neurological disorders. One possible reason for the vulnerability of myelin sheaths to damage became apparent from analyses of animals with altered amounts of otherwise normal myelin components: Due to limited redundance in function between different myelin proteins, dysfunction or loss of one protein may cause loss of function and instability of the entire myelin sheath.


Myelin Basic Protein Myelin Sheath Myelin Protein Proteolipid Protein Axonal Conduction 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Bagasra O, Michaels FH, Zheng YM, Bobroski LE, Spitsin SV, Fu ZF, Tawadros R, Koprowski H (1995) Activation of the inducible form of nitric oxide synthase in the brains of patients with multiple sclerosis. Proc Natl Acad Sci USA 92: 12041–12045.PubMedCrossRefGoogle Scholar
  2. Bartsch U, Bandtlow CE, Schnell L, Bartsch S, Spillmann AA, Rubin BP, Hillenbrand R, Montag D, Schwab ME, and Schachner M (1995) Lack of evidence that the myelinassociated glycoprotein (MAG) is a major inhibitor of axonal regeneration in the CNS. Neuron 15: 1375–1382.PubMedCrossRefGoogle Scholar
  3. Boison D, Stoffel W (1989) Myelin deficient rat: A point mutation in exon III (A > C, Thr75 > Pro) of the myelin proteolipid protein causes dysmyelination and oligodendrocyte death. EMBO J 8: 3295–3302.PubMedGoogle Scholar
  4. Boison D, Stoffel W (1994) Disruption of the compacted myelin sheath of axons of the central nervous system in proteolipid protein-deficient mice. Proc Natl Acad Sci USA 91: 11709–11713.PubMedCrossRefGoogle Scholar
  5. Boison D, Büssow H, D’Urso D, Müller HW, Stoffel W (1995) Adhesive properties of proteolipid protein are responsible for the compaction of CNS myelin sheaths. J Neurosci 15: 5502–5513.PubMedGoogle Scholar
  6. Bosio A, Binczek E, Stoffel W (1996) Functional breakdown of the lipid bilayer of the myelin membrane in central and peripheral nervous system by disrupted galactocerebroside synthesis. Proc Natl Acad Sci USA 93: 13280–13285.PubMedCrossRefGoogle Scholar
  7. Bö L, Quarles RH, Fujita N, Bartoszewicz Z, Sato S, Trapp BD (1995) Endocytic depletion of L-MAG from CNS myelin in quaking mice. J Cell Biol 131: 1811–1820.PubMedCrossRefGoogle Scholar
  8. Brett R, Rumsby MG (1993) Evidence of free radical damage in the central nervous system of guinea pigs at the prolonged acute and early relapse stages of chronic relapsing experimental allergic encephalomyelitis. Neurochem Int 23: 35–44.PubMedCrossRefGoogle Scholar
  9. Coetzee T, Fujita N, Dupree J, Shi R, Blight A, Szuzuki K, Suzuki K, Popko B (1996) Myelination in the absence of galactocerebroside and sulfatide: Normal structure with abnormal function and regional instability. Cell 86: 209–219.PubMedCrossRefGoogle Scholar
  10. Corbin JG, Kelly D, Rath EM, Baerwald KD, Suzuki K, Popko B (1996) Targeted CNS expression of interferon-y in transgenic mice leads to hypomyelination, reactive gliosis, and abnormal cerebellar development. Mol Cell Neurosci 7: 354–370.PubMedCrossRefGoogle Scholar
  11. Dietzschold B, Schwaeble W, Schäfer MK-H, Hooper DC, Zehng YM, Petry F, Sheng H, Fink T, Loos M, Koprowski H, Weihe E (1995) Expression of C1q, a subcomponent of the rat complement system, is dramatically enhanced in brains with either Borna disease or experimental allergic encephalomyelitis. J Neurol Sci 130: 11–16.PubMedCrossRefGoogle Scholar
  12. Duncan ID (1995) Inherited disorders of myelination of the central nervous system. In: Kettenmann H, Ransom B (eds) Neuroglia. Oxford University Press, Oxford, U.K., pp. 990–1009.Google Scholar
  13. Dupree JL, Coetzee T, Blight A, Suzuki K, Popko B (1998) Myelin galactolipids are essential for proper node of Ranvier formation in the CNS. J Neurosci 18: 1642–1649.PubMedGoogle Scholar
  14. Ebersole TA, Chen Q, Justice MJ, Artzt K (1996) The quaking gene product necessary in embryogenesis and myelination combines features of RNA binding and signal transduction proteins. Nat Genet 12: 260–265.PubMedCrossRefGoogle Scholar
  15. Erickson HP (1993) Gene knockouts of c-src, transforming growth factor b1, and tenascin suggest superfluous, nonfunctional expression of proteins. J Cell Biol 120: 1079–1081.PubMedCrossRefGoogle Scholar
  16. Fleming JO, Wang FI, Trousdale MD, Hinton DR, Stohlman SA (1993) Interaction of immune and central nervous systems: Contribution of anti-viral Thy-1+ cells to demyelination induced by Coronavirus JHM. Reg Immunol 5: 37–43.PubMedGoogle Scholar
  17. Fruttiger M, Montag D, Schachner M, Martini R (1995) Crucial role for the myelinassociated glycoprotein in the maintenance of axon-myelin integrity. Eur J Neurosci 7: 511–515.PubMedCrossRefGoogle Scholar
  18. Fujita N, Sato S, Ishigura H, Inuzuka T, Baba H, Kurihara T, Takahashi Y, Miyatake T (1990) The large isoform of myelin-associated glycoprotein is scarcely expressed in the quaking mouse brain. J Neurochem 55: 1056–1059.PubMedCrossRefGoogle Scholar
  19. Fujita N, Kemper A, Dupree J, Nakayasu H, Bartsch U, Schachner M, Maeda N, Suzuki K, Suzuki K, Popko B (1998) The cytoplasmic domain of the large myelin-associated glycoprotein isoform is needed for proper CNS but not peripheral nervous system myelination. J Neurosci 18: 1970–1978.PubMedGoogle Scholar
  20. Gow A, Friedrich VL, Lazzarini RA (1994) Many naturally occurring mutations of myelin proteolipid protein impair its intracellular transport. J Neurosci Res 37: 574–583.PubMedCrossRefGoogle Scholar
  21. Gravel M, Peterson J, Yong VW, Kottis V, Trapp BD, Braun PE (1996) Overexpression of 2′,3′-cyclic nucleotide 3′-Phosphodiesterase in transgenic mice alters oligodendrocyte development and produces aberrant myelination. Mol Cell Neurosci 7: 453–466.PubMedCrossRefGoogle Scholar
  22. Johnson RS, Roder JC, Riordan JR (1995) Over-expression of the DM-20 myelin proteolipid causes central nervous system demyelination in transgenic mice. J Neurochem 64: 967–976.PubMedCrossRefGoogle Scholar
  23. Kagawa T, Ikenaka K, Inoue Y, Kuriyama S, Tsujii T, Nakao J, Nakajima K, Aruga J, Okano H, Mikoshiba K (1994) Glial cell degeneration and hypomyelination caused. by overexpression of myelin proteolipid protein gene. Neuron 13: 427–442.PubMedCrossRefGoogle Scholar
  24. Katsuki M, Sato M, Kimura M, Yokoyama M, Kobayashi K, Nomura T (1988) Conversion of normal behavior to shiverer by myelin basic protein antisense cDNA in transgenic mice. Science 241: 393–593.CrossRefGoogle Scholar
  25. Kelso A (1994) The enigma of cytokine redundancy. Immunol Cell Biol 72: 97–101.PubMedCrossRefGoogle Scholar
  26. Kimura M, Inoko H, Katsuki M, Ando A, Sato T, Hirose T, Takashima H, Inayama S, Okano H, Takamatsu K, Mikoshiba K, Tsukuda Y, Watanabe I (1985) Molecular genetic analysis of myelin deficient mice: Shiverer mutant mice show deletion in gene(s) coding for myelin basic protein (MBP). J Neurochem 44: 692–696.PubMedCrossRefGoogle Scholar
  27. Kimura M, Sato M, Akatsuka A, Nozawa-Kimura S, Takahashi R, Yokoyama N, Nomura T, Katsuki M (1989) Restoration of myelin formation by a single type of myelin basic protein (MBP) in transgenic shiverer mice. Proc Natl Acad Sci USA 86: 5661–5665.PubMedCrossRefGoogle Scholar
  28. Kitagawa K, Sinoway MP, Yang C, Gould RM, Colman DR (1993) A proteolipid protein gene family: Expression in sharks and rays and possible evolution from an ancestral gene encoding a pore-forming polympeptide. Neuron 11: 433–448.PubMedCrossRefGoogle Scholar
  29. Klugmann M, Schwab MH, Pühlhofer A, Schneider A, Zimmermann F, Griffiths IR, Nave K-A (1997) Assembly of CNS myelin in the absence of proteolipid protein. Neuron 18: 59–70.PubMedCrossRefGoogle Scholar
  30. Lassmann H, Bartsch U, Montag D, Schachner M (1997) Dying back oligodendrogliopathy: A late sequel of myelin-associated glycoprotein deficiency. Glia 19: 104–110.PubMedCrossRefGoogle Scholar
  31. Li C, Tropak MB, Gerlai R, Clapoff S, Abramow-Newerly W, Trapp BD, Peterson A, Roder J (1994) Myelination in the absence of myelin-associated glycoprotein. Nature 369: 747–750.PubMedCrossRefGoogle Scholar
  32. Linington C, Bradl M, Lassmann H, Brunner C, Vass K (1988) Augmentation of demyelination in rat acute allergie encephalomyelitis by circulating mouse monoclonal antibodies directed against a myelin/oligodendrocyte glycoprotein. Am J Pathol 130: 443–454.PubMedGoogle Scholar
  33. Mastronardi FG, Ackerley CA, Arsenault L, Roots BI, Moscarello MA (1993) Demyelination in a transgenic mouse: A model for multiple sclerosis. J Neurosci Res 36: 315–324.PubMedCrossRefGoogle Scholar
  34. Montag D, Giese KP, Bartsch U, Martini R, Lang Y, Bluethmann H, Karthigasan J, Kirschner DA, Wintergerst E, Nave K-A, Zielasek J, Toyka KV, Lipp H-P, Schachner M (1994) Mice deficient for the myelin-associated glycoprotein show subtle abnormalities in myelin. Neuron 13: 229–246.PubMedCrossRefGoogle Scholar
  35. Nave K-A (1995) Neurological mouse mutants: a molecular-genetic analysis of myelin proteins. In: Kettenmann H, Ransom B (eds) Neuroglia. Oxford University Press, Oxford, U.K., pp. 571–586.Google Scholar
  36. Nave K-A, Lai C, Bloom FE, Milner RJ (1986) Jimpy mutant mouse: A 74-base deletion in the mRNA for myelin proteolipid protein (PLP) and evidence for a primary defect in RNA splicing. Proc Natl Acad Sci USA 83: 9264–9268.PubMedCrossRefGoogle Scholar
  37. Popko B, Puckett C, Lai E, Shine HD, Readhead C, Takahashi N, Hunt III SW, Sidman R, Hood LE (1987) Myelin deficient mice: Expression of myelin basic protein and generation of mice with varying levels of myelin. Cell 48: 713–721.PubMedCrossRefGoogle Scholar
  38. Popko B, Puckett C, Hood LE (1988) A novel mutation in myelin-deficient mice results in unstable myelin basic protein gene transcripts. Neuron 1: 221–225.PubMedCrossRefGoogle Scholar
  39. Probert L, Akassoglou K, Pasparakis M, Kontogeorgos G, Kollias G (1995) Spontaneous inflammatory demyelinating disease in transgenic mice showing central nervous system-specific expression of tumor necrosis factor a. Proc Natl Acad Sci USA 92: 11294–11298.PubMedCrossRefGoogle Scholar
  40. Readhead C, Popko B, Takahashi N, Shine HD, Saavedra RA, Sidman RL, Hood L (1987) Expression of a myelin basic protein gene in transgenic shiverer mice: correction of the dysmyelinating phenotype. Cell 48: 703–712.PubMedCrossRefGoogle Scholar
  41. Readhead C, Schneider A, Griffiths I, Nave K-A (1994) Premature arrest of myelin formation in transgenic mice with increased proteolipid protein gene dosage. Neuron 12: 583–595.PubMedCrossRefGoogle Scholar
  42. Roach A, Boylan K, Horvath S, Prusiner SB, Hood LE (1983) Characterization of cloned cDNA representing rat myelin basic protein: Absence of expression in brain of shiverer mutant mice. Cell 34: 799–806.PubMedCrossRefGoogle Scholar
  43. Roach A, Takahashi N, Pravtcheva D, Ruddle F, Hood L (1985) Chromosomal mapping of mouse myelin basic protein gene and structure and transcription of the partially deleted gene in shiverer mutant mice. Cell 42: 149–155.PubMedCrossRefGoogle Scholar
  44. Rodriguez M (1985) Virus-induced demyelination in mice: “Dying-back” of oligodendrocytes. Mayo Clin Proc 60: 433–438.PubMedGoogle Scholar
  45. Rodriguez M, Pavelko KD, Njenga MK, Logan WC, Wettstein PJ (1996) The balance between persistent virus infection and immune cells determines demyelination. J Immunol 157: 5699–5709.PubMedGoogle Scholar
  46. Rosenbluth J, Stoffel W, Schiff R (1996) Myelin structure in proteolipid protein (PLP)-null mouse spinal cord. J Comp Neurol 371: 336–344.PubMedCrossRefGoogle Scholar
  47. Schäfer M, Fruttiger M, Montag D, Schachner M, Martini R (1996) Disruption of the gene for the myelin-associated glycoprotein improves axonal regrowth along myelin in C57BL/Wlds mice. Neuron 16: 1107–1113.PubMedCrossRefGoogle Scholar
  48. Scherer S (1997) Molecular genetics of demyelination: New wrinkles on an old membrane. Neuron 18: 13–16.PubMedCrossRefGoogle Scholar
  49. Shine HD, Readhead C, Popko B, Hood L, Sidman RL (1992) Morphometric analysis of normal, mutant, and transgenic CNS: Correlation of myelin basic protein expression to myelinogenesis. J Neurochem 58: 342–349.PubMedCrossRefGoogle Scholar
  50. Stoffel W, Boison D, Büssow H (1997) Functional analysis in vivo of the double mutant mouse deficient in both proteolipid protein (PLP) and myelin basic protein (MBP) in the central nervous system. Cell Tiss Res 289: 195–206.CrossRefGoogle Scholar
  51. Yan Y, Lagenaur C, Narayanan V (1993) Molecular cloning of M6: Identification of a PLP/DM20 gene family. Neuron 11: 423–431.PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag/Wien 1999

Authors and Affiliations

  • Monika Bradl
    • 1
  1. 1.Abteilung NeuroimmunologieMax-Planck-Institut für NeurobiologieMartinsriedFederal Republic of Germany

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