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Volume 16, Number 24, Issue of December 15, 1996 pp. 7920-7929
Copyright ©1996 Society for NeuroscienceMonoclonal Antibody O10 Defines a Conformationally Sensitive Cell-Surface Epitope of Proteolipid Protein (PLP): Evidence that PLP Misfolding Underlies Dysmyelination in Mutant Mice
Received Aug. 15, 1996; revised Sept. 30, 1996; accepted Oct. 3, 1996.
Martin Jung1, Ilse Sommer1, 2, Melitta Schachner3, and Klaus-Armin Nave1 1 Zentrum für Molekulare Biologie (ZMBH), Universität Heidelberg, D-69120 Heidelberg, Germany, 2 Marshfield Medical Research Foundation, Department of Medical Genetics, Marshfield, Wisconsin 54449, and 3 Department of Neurobiology, Swiss Federal Institute of Technology, Hönggerberg, CH-8012 Zürich, Switzerland
Mutations in the gene for proteolipid protein (PLP) have been associated with CNS dysmyelination and abnormal oligodendrocyte death in spontaneous mouse mutants and in Pelizaeus-Merzbacher disease; however, the effect of mutations on PLP structure and function are little understood. We have identified a monoclonal antibody directed against a novel cell surface epitope of PLP, termed O10. By immunofluorescence analysis, COS-7 cells transiently transfected to express PLP (or its isoform DM20) can be stained with antibody O10 and another antibody (A431) directed against the C terminus of PLP/DM20. The subcellular distribution of immunofluorescence labels for the two antibodies is not identical, suggesting that the O10 epitope is acquired post-translationally. When PLP/DM20 from jimpy, jimpymsd, and rumpshaker mutant mice is expressed in COS-7 cells and compared with wild-type PLP/DM20, none of the mutant isoforms displays the O10 epitope, whereas the C-terminal epitope is detected. Because the O10 but not the A431 epitope is also sensitive to SDS and reducing agents, this strongly suggests abnormal protein folding in the PLP mutants. PLP from jimpymsd mice is obviously misfolded, because the amino acid substitution (Ala242
Val) is located within a transmembrane domain to which the O10 antibody does not bind. We propose that the O10 epitope emerges as the full length protein reaches a functional tertiary structure and that the absence of this epitope marks a structural defect of PLP that leads to dysmyelination.
Key words: oligodendrocyte differentiation; myelin assembly; proteolipid protein; protein misfolding; apoptosis; jimpy mouse; rumpshaker mouse; Pelizaeus-Merzbacher disease
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