Summary
Proteolipid protein (PLP) is a major component of myelin in the central nervous system where it constitutes approximately 50% of the total myelin protein by mass. This alone suggests an important structural function of PLP in compact myelin. More recently, the application of molecular genetic techniques by several groups has revealed an unexpected complex relationship between the PLP structure (a multitopic integral membrane protein) and its cellular function(s) which appear to exceed that of a simple molecular “strut” in the compacted myelin sheath. In particular the identification of mutations in the X chromosome-linked PLP gene of several neurological mutants (jimpy, jimpy msd, and rumpshaker in mouse, md rat, shaking pup) as well as in human patients with Pelizaeus-Merzbacher disease has provided the opportunity to study an unexpected role of PLP in normal oligodendrocyte development and its involvement in genetic dysmyelinating diseases. Finally, the generation of transgenic mice has yielded a surprising demonstration that the accurate expression level of the PLP gene is a major determinant of normal myelination in vivo. The Pelizaeus-Merzbacher syndrome has also been associated with an interstitial duplication of the human X chromosome (region Xq13–23). PLP overexpressing transgenic mice prove experimentally that the dysmyelinated phenotype of this human chromosomal imbalance is most likely caused by the increased expression of a single developmentally regulated gene.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
G. Lemke, Unwrapping the genes of myelin, Neuron 1: 535 (1988).
R.J. Milner, C. Lai, K.-A. Nave, D. Lenoir, J. Ogata, and J.G. Sutcliffe, Nucleotide sequences of two mRNAs for rat brain myelin proteolipid protein, Cell 42: 931 (1985).
J.-L. Popot, D. Pham-Dinh, and A. Dautigny, Major myelin proteolipid: the 4-a-helix topology, J. Membr. Biol. 120: 233 (1991).
T. Weimbs and W. Stoffel, Proteolipid protein (PLP) of CNS myelin: positions of free, disulfide-bonded, and fatty acid thioester-linked cysteine residues and implications for the membrane topology of PLP, Biochem. 31: 12289 (1992).
K.-A. Nave, F. E. Bloom, and R. J. Milner, A single nucleotide difference in the gene for myelin proteolipid protein defines the jimpy mutation in mouse. J. Neurochem. 49: 1873 (1987).
K. Ikenaka, T. Kagawa, and K. Mikoshiba, Selective expression of DM-20, an alternatively spliced myelin proteolipid protein gene product, in developing nervous system and in nonglial cells, J. Neurochem. 58: 2248 (1992).
B. Kiefer, A. Schneider, and K.-A. Nave, Primary structure of two proteolipid protein isoforms from Xenopus laevis: unusual conservation of the membrane-spanning domains, (submitted).
K.-A. Nave, C. Lai, F.E. Bloom, and R.J. Milner, Jimpy mutant mouse: a 74-base deletion in the mRNA for myelin proteolipid protein and evidence for a primary defect in RNA splicing, Proc. Natl. Acad. Sci. USA 83: 9264 (1986).
L.D. Hudson, J.A. Berndt, C. Puckett, C.A. Kozak, and R.A. Lazzarini, Aberrant splicing of proteolipid protein mRNA in the dysmyelinating jimpy mutant mouse, Proc. Natl. Acad. Sci. USA 84: 1454 (1987).
W.B. Macklin, M.V. Gardinier, K.D. King, and K. Kampf, An AG =GG transition at a splice site in the myelin proteolipid protein gene in jimpy mice results in the removal of an exon, FEBS Lett. 223: 417 (1987).
A. Schneider, P. Montague, I. Griffiths, M. Fanarraga, P. Kennedy, P. Brophy, and K.-A. Nave, Uncoupling of hypomyelination and glial cell death by a mutation in the proteolipid protein gene, Nature 358: 758 (1992).
S. Gencic and L.D. Hudson, Conservative amino acid substitution in the gene encoding myelin proteolipid protein disrupts oligodendrocyte differentiation, J. Neurosci. 10: 117 (1990).
L.D. Hudson, C. Puckett, J. Berndt, J. Chan, and S. Gencic, Mutation of the proteolipid protein gene PLP in a human X chromosome-linked myelin disorder, Proc. Natl. Acad. Sci. USA 86: 8128 (1989).
J.A. Trofatter, S.R. Dlouhy, W. DeMyer, P.M. Conneally, and M.E. Hodes, Pelizaeus-Merzbacher disease: tight linkage to proteolipid protein gene variant, Proc. Natl. Acad. Sci. USA 86: 9427 (1989).
D. Pham-Dinh, J.-L. Popot, O. Boeseflug-Tanguy, P. Landrieu, J.-F. Deleuze, J. Boué, P. Joliés, and A. Dautigny, Pelizaeus-Merzbacher disease: a valine to phenylalanine point mutation in a putative extracellular loop of myelin proteolipid, Proc. Natl. Acad. Sci. USA 88: 7562 (1991).
E. Farkas-Bargeton, O. Robain, and P. Mandel, Abnormal glial maturation in the white matter in jimpy mice, Acta Neuropath. 21: 272 (1972).
R.P. Skoff, Increased proliferation of oligodendrocytes in the hypomyelinated mouse mutant jimpy, Brain Res. 248: 19 (1982).
P.E. Knapp, R.P. Skoff, and D.W. Redstone, Oligodendroglial cell death in jimpy mice: an explanation for the myelin deficit, J. Neurosci. 6: 2813 (1986).
I.D. Duncan, J.P. Hammang, S. Goda, and R.H. Quarles, Myelination in the jimpy mouse in the absence of proteolipid protein, Glia 2: 148 (1989).
S. Billings-Gagliardi, L.H. Adcock, and M.K. Wolf, Hypomyelinated mutant mice: description of jpmsd and comparison with jp and qk on their present genetic backgrounds, Brain Res. 194: 325 (1980).
M.L. Fanarraga, I.R. Griffiths, M.C. McCulloch, J.A. Barrie, P.G.E. Kennedy, and P.J. Brophy, Rumpshaker: an X-linked mutation causing hypomyelination: developmental differences in myelination and glial cells between the optic nerve and spinal cord, Glia 5: 161 (1992).
C. Readhead, A. Schneider, I. Griffiths, and K.-A. Nave, Dysmyelination and astrocytosis in transgenic mice overexpressing the proteolipid protein gene, (submitted).
A. Schneider, I. Griffiths, C. Readhead, and K.-A. Nave, Dominant-negative action of the jimpy mutation in the mouse proteolipid protein gene, (submitted).
K. Ikenaka, (personal communication).
D.J. Wohlgemuth, R.R. Behringer, M.P. Mostoller, R.L. Brinster, and R.D. Palmiter, Transgenic mice overexpressing the mouse homeobox-containing gene Hox-1.4 exhibit abnormal gut development, Nature 337: 464 (1989).
W.H. Raskind, CA. Williams, L.D. Hudson, and T.D. Bird, Complete deletion of the proteolipid protein gene (PLP) in a family with X-linked Pelizaeus-Merzbacher disease, Am. J. Hum. Genet. 49: 1355 (1991).
F.P.M. Cremers, R.A. Pfeiffer, T.J.R., van de Pol, M.H. Hofker, T.A. Kruse, B. Wieringa, and H.H. Ropers, An interstitial duplication of the X chromosome in a male allows physical fine mapping of probes from the Xq13-q22 region, Hum. Genet. 77: 23 (1987).
U. Suter, A.A. Welcher, T. Özcelik, GJ. Snipes, B. Kosaras, U. Francke, S. Billings-Gagliardi, R.L. Sidman, and E.M. Shooter, Trembler mouse carries a point mutation in a myelin gene Nature 356: 241 (1992).
P.I. Patel, B.B. Roa, A.A. Welcher, R. Schoener-Scott, B.J. Trask, L. Pentao, G. Jackson Snipes, C.A. Garcia, U. Francke, E.M. Shooter, J.R. Lupski, and U. Suter, The gene for the peripheral myelin protein PMP-22 is a candidate for Charcot-Marie-Tooth disease type 1 A, Nature Genet. 1: 159 (1992).
V. Timmerman, E. Nelis, W. Van Hul, B.W. Nieuwenhuijsen, K.L. Chen, S. Wang, K. Ben Othman, B. Cullen, R.J. Leach, C.O. Hanemann, P. De Jonghe, P. Raeymaekers, G.-J.B. van Ommen, J.-J. Martin, H.W. Müller, J.M. Vance, K.H. Fischbeck, and C Van Broeckhoven, Myelin gene PMP-22/gas-3 is contained within the Charcot-Marie-Tooth disease type 1a duplication, Nature Genet. 1: 171 (1992).
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 1994 Springer Science+Business Media New York
About this chapter
Cite this chapter
Nave, KA. et al. (1994). Molecular Biology and Neurogenetics of Myelin Proteolipid Protein. In: Salvati, S. (eds) A Multidisciplinary Approach to Myelin Diseases II. NATO ASI Series, vol 258. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-2435-9_12
Download citation
DOI: https://doi.org/10.1007/978-1-4615-2435-9_12
Publisher Name: Springer, Boston, MA
Print ISBN: 978-1-4613-6034-6
Online ISBN: 978-1-4615-2435-9
eBook Packages: Springer Book Archive