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A cellular mechanism governing the severity of Pelizaeus–Merzbacher disease

Nature Genetics volume 13, pages 422–428 (1996)Cite this article

Abstract

Pelizaeus–Merzbacher disease (PMD) is a leukodystrophy linked to the proteolipid protein gene (PLP). We report a cellular basis for the distinction between two disease subtypes, classical and connatal, based on protein trafficking of the two PLP gene products (PLP and DM20). Classical PMD mutations correlate with accumulation of PLP in the ER of transfected COS–7 cells while the cognate DM20 traverses the secretory pathway to the cell surface. On the other hand, connatal PMD mutations lead to the accumulation of both mutant PLP and DM20 proteins in the ER of COS–7 cells with little of either isoform transported to the cell surface. Moreover, we show that transport–competent mutant DM20s facilitate trafficking of cognate PLPs and hence may influence disease severity.

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References

  1. Boespflug-Tanguy, O. et al. Genetic homogeneity of Pelizaeus-Merzbacher disease: tight linkage to the proteolipoprotein locus in 16 affected families. Am. J. Hum. Genet. 55, 461–467 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Modes, M., Pratt, V. & Dlouhy, S. Genetics of Pelizaeus-Merzbacher disease. Dev. Neurosci. 15, 383–394 (1993).

    Article  Google Scholar 

  3. Hodes, M. & Dlouhy, S. The changing phenotype of Pelizaeus-Merzbacher disease. Am. J. Hum. Genet. 57, A92 (1995).

    Google Scholar 

  4. McKusick, V., Mendlian inheritance in Man. (Johns Hopkins University Press, Baltimore, 1994).

    Google Scholar 

  5. Kaye, E., Doll, R., Natowicz, M. & Smith, F. Pelizaeus-Merzbacher disease presenting as spinal muscular atrophy: clinical and molecular studies. Ann. Neurol. 36, 916–919 (1994).

    Article  CAS  Google Scholar 

  6. Nance, M. et al. Adult-onset neurological disorder in a Pelizaeus-Merzbacher disease carrier mother. Am. J. Hum. Genet. 53, 1745 (1993).

    Google Scholar 

  7. Kobayashi, H., Hoffman, E. & Marks, H. The rumpshaker mutation in spastic paraplegia. Nature Genet. 7, 351–352 (1994).

    Article  CAS  Google Scholar 

  8. Saugier-Veber, P. et al. X-linked spastic paraplegia and Pelizaeus-Merzbacher disease are allelic disorders at the proteolipid protein locus. Nature Genet. 6, 257–262 (1994).

    Article  CAS  Google Scholar 

  9. Hudson, L.D. & Nadon, N.L. in Myelin: Biology and Chemistry. (ed. Martenson, R.E.) 677–702 (CRC Press, Boca Raton, 1992).

    Google Scholar 

  10. Skoff, R. & Knapp, P. in Myelin: Biology and Chemistry. (ed. Martenson, R.) 653–676 (CRC Press, Boca Raton, 1992).

    Google Scholar 

  11. Gow, A., Friedrich, V., Jr. & Lazzarini, R. Intracellular transport and sorting of the oligodendrocyte transmembrane proteolipid protein. J. Neurosci. Res. 37, 563–573 (1994).

    Article  CAS  Google Scholar 

  12. Gow, A., Friedrich, V. Jr. & Lazzarini, R. Many naturally occurring mutations of myelin proteolipid protein impair its intracellular transport. J. Neurosci. Res. 37, 574–583 (1994).

    Article  CAS  Google Scholar 

  13. Rose, J.K. & Doms, R.W. Regulation of protein export from the endoplasmic reticulum. Annu. Rev. Cell Biol. 4, 257–288 (1988).

    Article  CAS  Google Scholar 

  14. Hammond, C. & Helenius, A. Quality control in the secretory pathway. Curr. Opin. Cell Biol. 7, 523–529 (1995).

    Article  CAS  Google Scholar 

  15. Schneider, A. et al. Uncoupling of hypomyelination and glial cell death by a mutation in the proteolipid protein gene. Nature 358, 758–761 (1992).

    Article  CAS  Google Scholar 

  16. Billings-Gagliardi, S., Adcock, L.H. & Wolf, M.K. Hypomyelinated mutant mice: description of jpmsd and comparison with jp and qk on their present genetic backgrounds. Brain Res. 194, 325–338 (1980).

    Article  CAS  Google Scholar 

  17. Mitchell, L. et al. Developmental expression of major myelin protein genes in the CMS of X-linked hypomyelinating mutant rumpshaker. J. Neurosci. Res. 33, 205–217 (1992).

    Article  CAS  Google Scholar 

  18. Tosic, M., Dolivo, M., Amiguet, P., Domanska-Janik, K. & Matthieu, J.-M. Paralytic tremor (pt) rabbit: a sex-linked mutation affecting proteolipid protein-gene expression. Brain Res. 625, 307–312 (1993).

    Article  CAS  Google Scholar 

  19. Tosic, M., Dolivo, M., Amiguet, P., Domanska-Janik, K. & Matthieu, J.-M. Paralytic tremor (pt): a new allele of the proteolipid protein gene in rabbits. J. Neurochem. 63, 2210–2216 (1994).

    Article  CAS  Google Scholar 

  20. Gething, M.-J. & Sambrook, J. Transport and assembly processes in the endoplasmic reticulum. Semin. Cell Biol. 1, 65–72 (1990).

    CAS  PubMed  Google Scholar 

  21. Tosic, M. et al. Proteolipid/DM20 proteins bearing the paralytic tremor mutation in peripheral nerves and transfected Cos-7 cells. Neurochem. Res. 21, 423–430 (1996).

    Article  CAS  Google Scholar 

  22. Raposo, G., Van Santen, H., Leijendekker, R., Geuze, H. & Ploegh, H. Misfolded major histocompatibility complex class I molecules accumulate in an expanded ER-Golgi intermediate compartment. J. Cell Biol. 131, 1403–1419 (1995).

    Article  CAS  Google Scholar 

  23. Hammond, C. & Helenius, A. Quality control in the secretory pathway: retention of a misfolded viral membrane glycoprotein involves cycling between the ER, intermediate compartment and Golgi apparatus. J. Cell Biol. 126, 41–52 (1994).

    Article  CAS  Google Scholar 

  24. Sinoway, M., Kitagawa, K., Timsit, S., Hashim, G. & Colman, D. Proteolipid protein interactions in transfectants: implications for myelin assembly. J. Neurosci. Res. 37, 551–562 (1994).

    Article  CAS  Google Scholar 

  25. Hurtley, S.M. & Helenius, A. Protein oligomerization in the endoplasmic reticulum. Annu. Rev. Cell Biol. 5, 277–307 (1989).

    Article  CAS  Google Scholar 

  26. Puckett, C. et al. Myelin-specific proteolipid protein is expressed in myelinating Schwann cells but is not incorporated into myelin sheaths. J. Neurosci. Res. 18, 511–518 (1987).

    Article  CAS  Google Scholar 

  27. Bonifacino, J. & Lippincott-Schwartz, J. Degradation of proteins within the endoplasmic reticulum. Curr. Biol. 3, 592–600 (1991).

    Article  CAS  Google Scholar 

  28. Ward, C., Omura, S. & Kopito, R. Degradation of CFTR by the ubiquitin-proteasome pathway. Cell 83, 121–127 (1995).

    Article  CAS  Google Scholar 

  29. Jensen, T. et al. Multiple proteolytic systems, including the proteasome, contribute to CFTR processing. Cell 83, 129–135 (1995).

    Article  CAS  Google Scholar 

  30. Wu, Y. et al. A lag in intracellular degradation of mutant α1-antitrypsin correlates with the liver disease phenotype in homozygous PiZZ α1 antitrypsin deficiency. Proc. Natl. Acad. Sci. USA 91, 9014–9018 (1994).

    Article  CAS  Google Scholar 

  31. Milner, R. et al. Nucleotide sequences of two mRNAs for rat brain myelin proteolipid protein. Cell 42, 931–939 (1985).

    Article  CAS  Google Scholar 

  32. Pfeiffer, S., Warrington, A. & Bansal, R. The oligodendrocyte and its many cellular processes. Trends Cell Biol. 3, 191–197 (1993).

    Article  CAS  Google Scholar 

  33. Ellis, D. & Malcolm, S. Proteolipid protein gene dosage effect in Pelizaeus-Merzbacher disease. Nature Genet. 6, 333–334 (1994).

    Article  CAS  Google Scholar 

  34. Kagawa, T. et al. Glial cell degeneration and hypomyelination caused by overexpression of myelin proteolipid protein gene. Neuron 13, 427–442 (1994).

    Article  CAS  Google Scholar 

  35. Readhead, C., Schneider, A., Griffiths, I. & Nave, K.A. Premature arrest of myelin formation in transgenic mice with increased proteolipid protein gene dosage. Neuron 12, 583–595 (1994).

    Article  CAS  Google Scholar 

  36. Nussbaum, J.L. & Roussel, G. Immunocytochemical demonstration of the transport of myelin proteins through the Golgi apparatus. Cell Tissue Res. 234, 547–559 (1983).

    Article  CAS  Google Scholar 

  37. Roussel, G., Meskovic, N., Trifilieff, E., Artault, J.-C. & Nussbaum, J.-L. Arrest of proteolipid transport through the Golgi apparatus in Jimpy brain. J. Neurocytol. 16, 195–204 (1987).

    Article  CAS  Google Scholar 

  38. Watanabe, I. et al. Early lesion of Pelizaeus-Merzbacher disease: electron microscopic and biochemical study. J. Neuropath. Exp. Neurol. 32, 313–333 (1973).

    Article  CAS  Google Scholar 

  39. Duncan, I.D., Griffiths, I.R. & Munz, M. ‘Shaking pups’: a disorder of central myelination in the Spaniel dog. III. Quantitative aspects of glia and myelin in the spinal cord and optic nerve. Neuropathol. Appl. Neurobiol. 9, 355–368 (1983).

    Article  CAS  Google Scholar 

  40. Dentinger, M.P., Barron, K.D. & Csiza, C.K. Ultrastructure of the central nervous system in a myelin deficient rat. J. Neurocytol. 11, 671–691 (1982).

    Article  CAS  Google Scholar 

  41. Griffiths, I.R. et al. Rumpshaker mouse: a new X-linked mutation affecting myelination: evidence for a defect in PLP expression. J. Neurocytol. 19, 273–283 (1990).

    Article  CAS  Google Scholar 

  42. Yoshioka, T., Feigenbaum, L. & Jay, G. Transgenic mouse model for central nervous system demyelination. Molec. cell. Biol. 11, 5479–5486 (1991).

    Article  CAS  Google Scholar 

  43. Turnley, A.M. et al. Dysmyelination in transgenic mice resulting from expression of class I histocompatibility molecules in oligodendrocytes. Nature 353, 566–569 (1991).

    Article  CAS  Google Scholar 

  44. Raskind, W.H., Williams, C.A., Hudson, L.D. & Bird, T.D. Complete deletion of the proteolipid protein gene (PLP) in a family with X-linked Pelizaeus-Merzbacher disease. Am. J. Hum. Genet. 49, 1355–1360 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Boison, D. & Stoffel, W. 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).

    Article  CAS  Google Scholar 

  46. Boison, D., Bussow, H., D'Urso, D., Muller, H.-W. & Stoffel, W. Adhesive properties of proteolipid protein are responsible for the compaction of CNS myelin sheaths. J. Neurosci. 15, 5502–5513 (1995).

    Article  CAS  Google Scholar 

  47. Weimbs, T. & Stoffel, W. 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 PLR. Biochemistry 31, 12289–12296 (1992).

    Article  CAS  Google Scholar 

  48. Scheffer, I., Baraitser, M., Harding, W., Kendall, B. & Brett, E. Pelizaeus-Merzbacher disease: classical or connatal. Neuropediatrics 22, 71–78 (1991).

    Article  CAS  Google Scholar 

  49. Seitelberger, F. in Handbook of Clinical Neurology: Leukodystrophies and Polydystrophies. (eds. Vinken, R & Bruyn, G.) 150–202 (North-Holland, Amsterdam, 1970).

    Google Scholar 

  50. Boulloche, J. & Aicardi, J. Pelizaeus-Merzbacher disease: clinical and nosological study. J. Child Neurol. 1, 223–239 (1986).

    Article  Google Scholar 

  51. Timsit, S. et al. The DM20 protein of myelin: intracellular and surface expression patterns in transfectants. J. Neurochem. 58, 1936–1942 (1992).

    Article  CAS  Google Scholar 

  52. Bole, D., Hendershot, L. & Kearney, J. Posttranslational association of immunoglobulin heavy chain binding protein with nascent heavy chains in nonsecreting and secreting hybridomas. J. Cell Biol. 102, 1558–1566 (1986).

    Article  CAS  Google Scholar 

  53. Mane, S. et al. Purification and characterization of human lysosomal membrane glycoproteins. Arch. Biochem. Biophys. 268, 360–378 (1989).

    Article  CAS  Google Scholar 

  54. Yamamura, T., Konola, J.T., Wekerle, H. & Lees, M.B. Monoclonal antibodies against myelin proteolipid protein: identification and characterization of two major determinants. J. Neurochem. 57, 1671–1680 (1991).

    Article  CAS  Google Scholar 

  55. Hudson, L., Friedrich, V.L. Jr., Behar, T., Dubois-Dalcq, M. & Lazzarini, R.A. The initial events in myelin synthesis: orientation of proteolipid protein in the plasma membrane of cultured oligodendrocytes. J. Cell Biol. 109, 717–727 (1989).

    Article  CAS  Google Scholar 

  56. Hudson, L., Puckett, C., Berndt, J., Chan, J. & Gencic, S. Mutation of the proteolipid protein gene PLP in a human X chromosome-linked myelin disorder. Proc. Natl. Acad. Sci. USA 86, 8128–8131 (1989).

    Article  CAS  Google Scholar 

  57. Koeppen, A. in Myelin: Biology and Chemistry. (ed. Martenson, R.) 703–721 (CRC Press, Boca Raton, 1992).

    Google Scholar 

  58. Strautnieks, S., Rutland, P., Winter, R.M., Baraitser, M. & Malcolm, S. Pelizaeus-Merzbacher disease: detection of mutations thr181→pro and Ieu223→pro in the proteolipid protein gene, and prenatal diagnosis. Am. J. Hum. Genet. 51, 871–878 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Weimbs, T., Dick, T., Stoffel, W. & Boltshauser, E. 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).

    Article  CAS  Google Scholar 

  60. Pratt, V. et al. A new mutation in the proteolipid protein (PLP) gene in a German family with Pelizaeus-Merzbacher disease. Am. J. Med. Genet. 38, 136–139 (1991).

    Article  CAS  Google Scholar 

  61. Doll, R., Natowicz, M.R., Schiffmann, R. & Smith, F.I. Molecular diagnostics for myelin proteolipid protein gene mutations in Pelizaeus-Merzbacher disease. Am. J. Hum. Genet. 51, 161–169 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Gencic, S., Abuelo, D., Ambler, M. & Hudson, L.D. Pelizaeus-Merzbacher disease: an X-linked neurologic disorder of myelin metabolism with a novel mutation in the gene encoding proteolipid protein. Am. J. Hum. Genet. 45, 435–442 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Pham-Dinh, D. et al. Pelizaeus-Merzbacher disease: a valine to phenylalanine point mutation in a putative extracellular loop of proteolipid. Proc.Natl. Acad. Sci. USA 88, 7562–7566 (1991).

    Article  CAS  Google Scholar 

  64. Gencic, S. & Hudson, L.D. Conservative amino acid substitution in the myelin proteolipid protein of jimpymsd mice. J. Neurosci. 10, 117–124 (1990).

    Article  CAS  Google Scholar 

  65. Popot, J.L., Pham Dinh, D. & Dautigny, A., Myelin proteolipid: the 4-alpha-helix topology. J. Membr. Biol. 120, 233–246 (1991).

    Article  CAS  Google Scholar 

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    Alexander Gow & Robert A. Lazzarini

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Gow, A., Lazzarini, R. A cellular mechanism governing the severity of Pelizaeus–Merzbacher disease. Nat Genet 13, 422–428 (1996). https://doi.org/10.1038/ng0896-422

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