Molecularbiology and -pathology of the oligodendroglia, myelin and myelination in Central Nervous System.
Myelin integral membrane protein: 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 oligodendrocytes.
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). This model is generally accepted today.
Molecular biology of oligodendrocytes and myelination
We cloned the mouse, rat and human PLP cDNA on the basis of the protein structure. The human, mouse, rat and chicken plp gene structure has been characterized. The human plp locus was allocated to chromosome Xq12-23. On the basis of this knowledge we studied X-linked dismyelinosis in rat. We defined the genetic defect of the md- (myelin deficient) rat and different forms of the human Pelizaeus Merzbacher dysmyelinosis as point mutations of plp as genetic basis in affected individuals.
Figure 1: Tetraspan topology of plp in myelin membrane.
Figure 2: PLP/DM20 depleted myelin protein pattern of the plp-/- mouse. Electronmicroscopy of optic nerve of wt and plp-/- mice.
S. Wahle, W. Stoffel (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
D. Boison, H. Büssow, D. D'Urso, H.-W. Müller and W. Stoffel (1995)
Adhesive properties of proteolipid protein are responsible for the compaction of CNS myelin sheaths
J. Neurosc., 15(8), 5502-5513
R. Gutierrez, D. Boison, U. Heinemann, W. Stoffel (1995)
Decompaction of CNS myelin leads to a reduction of the conduction velocity of action potentials in optic nerve.
Neurosc. Letters 195, 93-96
D. Boison, W. Stoffel (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
T. Weimbs, W. Stoffel (1994)
Topology of CNS myelin proteolipid protein. Evidence for the non-enzymatic glycosylation of extracytoplasmic domains in normal and diabetic animals
Biochem., 33, 10408-10415
R. Janz, W. Stoffel (1993)
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
T. Weimbs, W. Stoffel (1992)
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
T. Weimbs, T. Dick, W. Stoffel, E. Boltshauser (1990)
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
H.-J. Diehl, M. Schaich, R.-M. Budzinski, W. Stoffel (1986)
Individual exons encode the integral membrane domains of human myelin proteolipid protein
Proc. Natl. Acad. Sci. USA, 83, 9807-9811
M. Schaich, R.-M. Budzinski, W. Stoffel (1986)
Cloned proteolipid protein and myelin basic protein cDNA
Biol. Chem. Hoppe-Seyler, 367, 825-834
W. Stoffel, H. Giersiefen, H. Hillen, W. Schröder, B. Tunggal (1985)
Amino-acid sequence of human and bovine brain myelin proteolipid protein (lipophilin) is completely conserved
Biol. Chem. Hoppe-Seyler, 366, 627-635
W. Stoffel, H. Hillen, W. Schröder, R. Deutzmann (1982)
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
W. Stoffel, W. Schröder, H. Hillen, R. Deutzmann (1982)
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