Analyses of proteolipid protein mutants show levels of proteolipid protein regulate oligodendrocyte number and cell death in vitro and in vivo.
Previous tissue culture studies indicate that the level of native proteolipid protein (PLP) or mutated PLP regulates the number of oligodendrocytes (Olgs). The regulation of Olg number is most likely due to toxicity of over-expression of native PLP or mis-sense mutations of PLP. We tested, in vivo and in vitro, the hypothesis that the absence of native PLP or reduced amounts of mutated PLP leads to an increase in numbers of Olgs and a corresponding decrease in the number of apoptotic Olgs. In cultures derived from PLP deficient mice, the number of Olgs is twofold greater than in wild-type mice. In primary glial cultures or in enriched OLG cultures, in which the synthesis of native PLP is blocked using antisense technology, the number of apoptotic cells is several-fold reduced. Injection of PLP antisense oligodeoxynucleotides into jimpy (jp) mice reduces the number of dying glia in spinal cord 3x compared to controls, and increased the number of myelinated fibers. These studies demonstrate that inhibition of native or mutant PLP synthesis directly reduces apoptosis. The regulation of apoptosis by PLP gene expression occurs independently of myelination, indicating that the PLP gene has multiple primary functions.
Skoff
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RP
Department of Anatomy and Cell Biology, Wayne State University School of Medicine, Detroit MI 48201, USA. rskoff@med.wayne.edu
Saluja
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I
Bessert
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Yang
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D000818:Animals; D000963:Antimetabolites; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D001973:Bromodeoxyuridine; D002452:Cell Count; D016923:Cell Death; D002460:Cell Line; D049109:Cell Proliferation; D020287:In Situ Nick-End Labeling; D051379:Mice; D008808:Mice, Inbred CBA; D008816:Mice, Jimpy; D009154:Mutation / Q000502:physiology*; D004676:Myelin Basic Protein / Q000096:biosynthesis / Q000235:genetics; D009836:Oligodendroglia / Q000502:physiology*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010641:Phenotype; D011510:Proteolipids / Q000235:genetics* / Q000502:physiology*
D000963:Antimetabolites; D004676:Myelin Basic Protein; D016376:Oligonucleotides, Antisense; D011510:Proteolipids; D001973:Bromodeoxyuridine