title: Biochemistry and neuropathology of mice doubly deficient in synthesis and degradation of galactosylceramide.
abstract: We have generated mice doubly deficient in both synthesis and degradation of galactosylceramide by cross-breeding twitcher mice and galactosylceramide synthase (UDP-galactose:ceramide galactosyltransferase, CGT) knockout mice. The prediction that the phenotype of the doubly deficient mice should be the same as the cgt -/- mice, since the degrading enzyme should not be necessary if the substrate is not synthesized, proved to be only partially correct. In early stages of the disease, the doubly deficient mice (galc -/-, cgt -/-) were essentially indistinguishable from the cgt -/- mice. However, the doubly deficient mice had a much shorter life span than cgt -/- mice. Both galactosylceramide and galactosylsphingosine (psychosine), were undetectable in the brain of the cgt -/- and the doubly deficient mice. The characteristic twitcher pathology was never seen in the galc -/-, cgt -/- mice. However, after 43 days, neuronal pathology was observed in the brainstem and spinal cord. This late neuronal pathology has not been seen in the CGT knockout mice but has been described in some long surviving bone marrow-transplanted twitcher mice. Furthermore, the motor segment of the trigeminal nerve of the galc -/-, cgt -/- mice showed severe degeneration not seen in either twitcher or CGT knockout mice. Thus, the galc -/-, cgt -/- mice, while primarily showing the cgt -/- phenotype as predicted, develop late pathology that is seen only in twitcher mouse and also a unique pathology in the trigeminal nerve. These observations indicate that the functional relationship between galactosylceramidase and galactosylceramide synthase is complex.
authors.affiliation: Neuroscience Center, University of North Carolina School of Medicine, Chapel Hill 27599-7250, USA.
authors.forename: T
authors.initials: T
authors.lastname: Ezoe
authors.forename: M T
authors.initials: MT
authors.lastname: Vanier
authors.forename: Y
authors.initials: Y
authors.lastname: Oya
authors.forename: B
authors.initials: B
authors.lastname: Popko
authors.forename: J
authors.initials: J
authors.lastname: Tohyama
authors.forename: J
authors.initials: J
authors.lastname: Matsuda
authors.forename: K
authors.initials: K
authors.lastname: Suzuki
authors.forename: K
authors.initials: K
authors.lastname: Suzuki
mesh_terms: D000818:Animals; D001835:Body Weight; D001923:Brain Chemistry / Q000235:genetics; D001933:Brain Stem / Q000473:pathology; D002851:Chromatography, High Pressure Liquid; D017931:DNA Primers; D005260:Female; D005698:Galactosylceramidase / Q000235:genetics* / Q000378:metabolism; D005699:Galactosylceramides / Q000096:biosynthesis / Q000378:metabolism*; D007965:Leukodystrophy, Globoid Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D008136:Longevity; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008818:Mice, Neurologic Mutants; D008854:Microscopy, Electron; D009410:Nerve Degeneration / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D009474:Neurons / Q000201:enzymology / Q000473:pathology / Q000648:ultrastructure; D010641:Phenotype; D011609:Psychosine / Q000032:analysis; D014276:Trigeminal Nerve / Q000473:pathology
chemical_list: D017931:DNA Primers; D005699:Galactosylceramides; D011609:Psychosine; D005698:Galactosylceramidase