Laboratory of Molecular Neuroscience   printer friendly

Myelin membrane structure and
genetic defects of the oligodendrocyte

Molecular biology and - pathology of the oligodendroglia, myelin and myelination in Central Nervous System.
Proteolipid protein (PLP) and dysmyelinoses.

The advancement of molecular and cell biology directed the focus of our research toward the molecular organisation, development and molecular pathology of CNS myelin and oligodendrocyte.

A. The breakthrough in myelin research came from the elucidation of the amino acid sequence of the main integral membrane protein component of CNS myelin, proteolipid protein (PLP) and its isoform DM20 by regular chemical analysis in our laboratory. We established the four transmembrane domain (TMD) topology and the S-acylation sites (Figure 1), a model, which generally accepted today.

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Figure 1: Membrane topology of the tetra-span proteolipid proteins: PLP und DM20

Molecular biology of oligodendrocytes and myelination

We cloned the mouse, rat and human PLP cDNA on the basis of the protein structure. The plp-locus was allocated to chromosome Xq12-23. The human plp gene structure was isolated and completely sequenced. Also the myelin basic protein gene has been cloned and sequenced. On the basis of this knowledge we tackled the development of myelinogenesis and studied X-linked dysmyelinoses in rat such as the md- (myelin deficient) rat and different forms of the human Pelizaeus Mezbacher dysmyelinosis, caused by point mutations, which we detected in affected individuals.

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Figure 2: Pattern of myelin proteins of CNS of wt- and PLP/DM20-deficient mice

References
  1. Wahle, S. and Stoffel, W. 1998 Cotranslational Integration of Myelin Proteolipid Protein (PLP) into the Membrane of Endoplasmic Reticulum:Analysis of Topology by Glycosylation Scanning and Protease Domain Protection Assay GLIA 24, 226-235
  2. D. Boison, H. Büssow, D. D'Urso, H.-W. Müller and W. Stoffel Adhesive properties of proteolipid protein are responsible for the compaction of CNS myelin sheaths J. Neurosc., 15(8), 5502-5513 (1995)
  3. R. Gutierrez, D. Boison, U. Heinemann, W. Stoffel Decompaction of CNS myelin leads to a reduction of the conduction velocity of action potentials in optic nerve. Neurosc. Letters 195, 93-96 (1995)
  4. D. Boison, W. Stoffel 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 (1994)
  5. T. Weimbs, W. Stoffel Topology of CNS myelin proteolipid protein. Evidence for the non-enzymatic glycosylation of extracytoplasmic domains in normal and diabetic animals Biochem., 33, 10408-10415 (1994)
  6. R. Janz, W. Stoffel Characterization of a brain-specific SP1-like activity interacting with an unusual binding site within the myelin proteolipid protein promoter Biol. Chem. Hoppe-Seyler, 374, 507-517 (1993)
  7. T. Weimbs, W. Stoffel Proteolipid protein (PLP) of CNS myelin: positions of free, disulfide bonded, and fatty acid thioester-linked cysteine residues. Implications for the membrane topology of PLP Biochem., 31, 12289-12296 (1992)
  8. F. Schließ, W. Stoffel Evolution of the myelin integral membrane proteins of the central nervous system. Biol. Chem. Hoppe-Seyler, 372, 865-874 (1991)
  9. W. Stoffel The myelin membrane of the central nervous system. Essential macromolecular structure and function Angew. Chem. Int. Ed., 29, 958-976 (1990)
  10. T. Weimbs, T. Dick, W. Stoffel, E. Boltshauser A point mutation at the X-chromosomal proteolipid protein locus in Pelizaeus-Merzbacher disease leads to disruption of myelinogenesis Biol. Chem. Hoppe-Seyler, 371, 1175-1183 (1990)
  11. W. Stoffel, T. Subkowski, S. Jander Topology of proteolipid protein in the myelin membrane of central nervous system Biol. Chem. Hoppe-Seyler, 370, 165-176 (1989)
  12. R. Streicher, W. Stoffel The organization of the human myelin basic protein gene Biol. Chem. Hoppe-Seyler, 370, 503-510 (1989) D. Boison, W. Stoffel
  13. D. Boison, W. Stoffel Myelin-deficient rat: a point mutation in exon III (AgC, Thr75Pro) of the myelin proteolipid protein causes dysmyelination and oligodendrocyte death EMBO J., 8, 3295-3302 (1989)
  14. H.-J. Diehl, M. Schaich, R.-M. Budzinski, W. Stoffel Individual exons encode the integral membrane domains of human myelin proteolipid protein Proc. Natl. Acad. Sci. USA, 83, 9807-9811 (1986)
  15. M. Schaich, R.-M. Budzinski, W. Stoffel Cloned proteolipid protein and myelin basic protein cDNA Biol. Chem. Hoppe-Seyler, 367, 825-834 (1986)
  16. H.-J. Diehl, M. Schaich, R.-M. Budzinski, W. Stoffel Individual exons encode the integral membrane domains of human myelin proteolipid protein Proc. Natl. Acad. Sci. USA, 83, 9807-9811 (1986)
  17. W. Stoffel, H. Giersiefen, H. Hillen, W. Schröder, B. Tunggal Amino-acid sequence of human and bovine brain myelin proteolipid protein (lipophilin) is completely conserved Biol. Chem. Hoppe-Seyler, 366, 627-635 (1985)
  18. W. Stoffel, H. Hillen The primary structure of bovine brain myelin lipophilin (proteolipid apoprotein) Hoppe-Seyler's Zeitschr. Physiol. Chemie, 364, 1455-1466 (1983)
  19. W. Stoffel, W. Schröder, H. Hillen, R. Deutzmann Lipophilin (proteolipid apoprotein) of brain white matter. Purification and amino acid sequence studies of the four tryptophan fragments Hoppe-Seyler's Zeitschr. Physiol. Chemie, 363, 1397-1407 (1982)
  20. W. Stoffel, W. Schröder, H. Hillen, R. Deutzmann Analysis of the primary structure of the strongly hydrophobic brain myelin proteolipid apoprotein (lipophilin). Isolation and amino acid sequence determination of proteolytic fragments Hoppe-Seyler's Zeitschr. Physiol. Chemie, 363, 1117-1131 (1982)


July 12, 2011
Center for Biochemistry, Joseph-Stelzmann-Straße 52, D50931 Cologne
Suggestions and wishes: Budi Tunggal
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