Biochemistry and neuropathology of mice doubly deficient in synthesis and degradation of galactosylceramide

We have generated mice doubly deficient in both synthesis and degradation o f 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 ne cessary if the substrate is not synthesized, proved to be only partially co rrect. In early stages of the disease, the doubly deficient mice (galc (-/- ), cgt (-/-)) were essentially indistinguishable from the cgt (-/-) mice. H owever, the doubly deficient mice had a much shorter life span than cgt (-/ -) mice. Both galactosylceramide and galactosylsphingosine (psychosine), we re undetectable in the brain of the cgt (-/-) and the doubly deficient mice . The characteristic twitcher pathology was never seen in the gale (-/-), c gt (-/-) mice. However, after 43 days, neuronal pathology was observed in t he brainstem and spinal cord. This late neuronal pathology has not been see n in the CGT knockout mice but has been described in some long surviving bo ne marrow-transplanted twitcher mice. Furthermore, the motor segment of the trigeminal nerve of the gale (-/-) cgt (-/-) mice showed severe degenerati on not seen in either twitcher or CGT knockout mice. Thus, the gale (-/-) c gt (-/-) mice, while primarily showing the cgt (-/-) phenotype as predicted , develop late pathology that is seen only in twitcher mouse and also a uni que pathology in the trigeminal nerve. These observations indicate that the functional relationship between galactosylceramidase and galactosylceramid e synthase is complex. (C) 2000 Wiley-Liss, Inc.