title: The twitcher mouse. Central nervous system pathology after bone marrow transplantation.
abstract: Effects of bone marrow transplantation (BMT) on the pathology of the central nervous system were evaluated, at light and electron microscope levels, in the homozygous twitcher mouse (twi/twi), an authentic murine model of globoid cell leukodystrophy (GLD, Krabbe disease) in humans. In the twitcher mice with BMT examined at ages 44 and 71 days (transplanted at the day 9 to 12), degeneration of oligodendrocytes and myelin was still present. In these mice, oligodendrocytes and macrophages containing typical tubular and crystalloid inclusions of GLD were observed in the white matter, in particular that of the cerebellum, brainstem, and spinal cord. However, significant morphologic improvement was observed in the central nervous system of the twitcher with BMT which survived more than 100 days. In the cerebellum, brainstem, and spinal cord of these mice, myelin degeneration and infiltration of macrophages containing typical GLD inclusions were either absent or only rarely observed. Instead, many foamy macrophages, either scattered or clustered around blood vessels, were conspicuous. Many nerve fibers with thin myelin sheaths indicative of remyelination were present in the white matter. GLD inclusions were, however, still found in the cytoplasm of apparently remyelinating oligodendrocytes. These results suggest that the foamy macrophages are of donor origin, since they are able to digest degraded myelin components completely, because of a sufficient galactosylceramidase activity, and are contributing to the improvement of the central nervous system pathology in the twitcher mouse following BMT, by supplying the deficient enzyme, galactosylceramidase. However, the presence of inclusions in oligodendrocytes in the twitcher with BMT, even after 100 days of age indicates that the basic enzymatic defect involving oligodendrocytes could not be completely corrected with BMT.
authors.affiliation: Department of Pathology, University of North Carolina, Chapel Hill.
authors.forename: K
authors.initials: K
authors.lastname: Suzuki
authors.forename: P M
authors.initials: PM
authors.lastname: Hoogerbrugge
authors.forename: B J
authors.initials: BJ
authors.lastname: Poorthuis
authors.forename: D W
authors.initials: DW
authors.lastname: Bekkum
authors.forename: K
authors.initials: K
authors.lastname: Suzuki
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D001921:Brain / Q000473:pathology* / Q000648:ultrastructure; D001933:Brain Stem / Q000473:pathology / Q000648:ultrastructure; D002531:Cerebellum / Q000473:pathology / Q000648:ultrastructure; D004195:Disease Models, Animal; D005260:Female; D005487:Foam Cells / Q000648:ultrastructure; D007965:Leukodystrophy, Globoid Cell / Q000473:pathology*; D008297:Male; D051379:Mice; D008818:Mice, Neurologic Mutants; D008854:Microscopy, Electron; D009186:Myelin Sheath / Q000473:pathology / Q000648:ultrastructure; D009836:Oligodendroglia / Q000473:pathology / Q000648:ultrastructure; D013116:Spinal Cord / Q000473:pathology* / Q000648:ultrastructure