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J. Cell Biol.,
Volume 140, Number 4, February 23, 1998 925-934
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.
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