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© The Rockefeller University Press, 0021-9525/1998//925 $5.00
The Journal of Cell Biology, Volume 140, Number 4, , 1998 925-934

Disrupted Proteolipid Protein Trafficking Results in Oligodendrocyte Apoptosis in an Animal Model of Pelizaeus-Merzbacher Disease

Brookdale Center for Developmental and Molecular Biology, Mount Sinai School of Medicine, New York 10029-6574

Abstract. Pelizaeus-Merzbacher disease (PMD) is a dysmyelinating disease resulting from mutations, deletions, or duplications of the proteolipid protein (PLP) gene. Distinguishing features of PMD include pleiotropy and a range of disease severities among patients. Previously, we demonstrated that, when expressed in transfected fibroblasts, many naturally occurring mutant PLP alleles encode proteins that accumulate in the endoplasmic reticulum and are not transported to the cell surface. In the present communication, we show that oligodendrocytes in an animal model of PMD, the msd mouse, accumulate Plp gene products in the perinuclear region and are unable to transport them to the cell surface. Another important aspect of disease in msd mice is oligodendrocyte cell death, which is increased by two- to threefold. We demonstrate in msd mice that this death occurs by apoptosis and show that at the time oligodendrocytes die, they have differentiated, extended processes that frequently contact axons and are expressing myelin structural proteins. Finally, we define a hypothesis that accounts for pathogenesis in most PMD patients and animal models of this disease and, moreover, can be used to develop potential therapeutic strategies for ameliorating the disease phenotype.

1. Abbreviations used in this paper: CNS, central nervous system; DAPI, 4',6-diamidino-2-phenylindole; MBP, myelin basic protein; PDGFR, platelet derived growth factor –receptor; PLP, proteolipid protein; PMD, Pelizaeus-Merzbacher disease; TdT, terminal transferase.

We thank: V. Friedrich, Jr and Susan Morgello for many helpful discussions involving neuroanatomy, morphometry, and statistics; Kazu Ikenaka and Marjorie Lees for providing us with the PLP antibodies; and Hans Lassmann and Helena Breitschopf for sharing their unpublished methods on terminal transferase labeling and in situ hybridization.

This work was supported by research grants awarded to A. Gow from the National Multiple Sclerosis Society (RG2891A1/1) and to R.A. Lazzarini from the National Multiple Sclerosis Society (RG2734-A3) and the National Institutes of Health (3P01NS33165-O1A1S1). This is manuscript number 248 from the Brookdale Center for Developmental and Molecular Biology, Mount Sinai School of Medicine.

Address all correspondence to R.A. Lazzarini, Brookdale Center for Developmental and Molecular Biology, Box 1126, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029-6574. Tel.: (212) 241-4272. Fax: (212) 860-9279. E-mail: rlazzar{at}smtplink.mssm.edu

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