Abstract
BackgroundArylsulfatase A (ASA)-deficient mice are a model for the lysosomal storage disorder metachromatic leukodystrophy. This lipidosis is characterised by the lysosomal accumulation of the sphingolipid sulfatide. Storage of this lipid is associated with progressive demyelination. We have mated ASA-deficient mice with mice heterozygous for a non-functional allele of UDP-galactose:ceramide-galactosyltransferase (CGT). This deficiency is known to lead to a decreased synthesis of galactosylceramide and sulfatide, which should reduce sulfatide storage and improve pathology in ASA-deficient mice.ResultsASA-/- CGT+/- mice, however, showed no detectable decrease in sulfatide storage. Neuronal degeneration of cells in the spiral ganglion of the inner ear, however, was decreased. Behavioural tests showed small but clear improvements of the phenotype in ASA-/- CGT+/- mice.ConclusionThus the reduction of galactosylceramide and sulfatide biosynthesis by genetic means overall causes modest improvements of pathology.
Highlights
Metachromatic leukodystrophy (MLD) is a lysosomal storage disease of humans, which is characterised by progressive demyelination
The underlying defect is the deficiency of arylsulfatase A (ASA), which results in the lysosomal accumulation of the sphingolipid 3-O-sulfogalactosylceramide predominantly in brain, kidney and bile ducts [1]
Brain lipid analysis of ASA-deficient mice heterozygous for a non-functional CGT allele To investigate whether a decrease in galactosylceramide and sulfatide synthesis can improve the phenotype of ASA-deficient mice we crossed ASA-/- with CGT+/- mice
Summary
Metachromatic leukodystrophy (MLD) is a lysosomal storage disease of humans, which is characterised by progressive demyelination. The underlying defect is the deficiency of arylsulfatase A (ASA), which results in the lysosomal accumulation of the sphingolipid 3-O-sulfogalactosylceramide (sulfatide) predominantly in brain, kidney and bile ducts [1]. Since MLD naturally only occurs in humans a mouse model was generated by targeted disruption of the ASA gene [2]. These animals store sulfatide in the same tissues as humans, including oligodendrocytes, Schwann cells and various neurons [2,3,4]. The accumulation of sulfatide in the central nervous system steadily (page number not for citation purposes)
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