Delay of myelin formation in arylsulphatase A‐deficient mice

Abstract

Metachromatic leukodystrophy (MLD) is a lysosomal storage disorder caused by the deficiency of arylsulphatase A (ASA). This leads to the accumulation of the sphingolipid 3-O-sulphogalactosylceramide (sulphatide) and progressive demyelination in the nervous system of MLD patients. The mechanisms and development of pathology in the disease are still largely unknown. In this study we investigate how the inability to degrade sulphatide affects the formation of myelin in ASA-deficient (ASA-/-) mice. In mice at 2 weeks of age there was a substantial reduction in myelin basic protein (MBP) mRNA and protein. This was confirmed by an immunohistochemical analysis. MBP mRNA and protein, however, reach normal levels at 3 weeks of age. Proteolipid protein (PLP) and MAL mRNA were also reduced in ASA-/- mice at 2 weeks of age; whereas the level of PLP mRNA was normal at 26 weeks of age, MAL mRNA expression remained reduced up to this age. In situ hybridization revealed no significant changes in the number of myelinating oligodendrocytes or oligodendrocyte precursor cells in ASA-/- mice. These results suggest that oligodendrocyte differentiation was normal in ASA-/- mice. No differences were found in the expression of the sulphatide synthesizing enzymes cerebroside sulphotransferase and UDP-galactose : ceramide galactosyltransferase. Our data demonstrate a delay in myelin formation in ASA-/- mice. This raises the possibility that similar alterations in MLD patients may contribute to the pathology of the disease.

Oligodendroglial Progenitor Cell Therapy Limits Central Neurological Deficits in Mice with Metachromatic Leukodystrophy

“…Furthermore, transplantation of MLD OLPs showed that ARSA deficiency did not influence the migratory capacity of the mutant OLPs. This result shows that the pathogenesis of MLD mice is not caused by deficient colonization of white matter territories by endogenous OLPs (Yaghootfam et al, 2005) nor caused by a toxic effect from the MLD brain environment. Instead, it suggests that pathogenesis is caused by a cellautonomous defect of ARSA deficiency after cell migration.…”

“…Furthermore, it is unclear whether the accumulation of sulfatides in perinatal OLPs in the MLD mouse model, which might still be at a low concentration at the time of the transplantation, has an impact on their survival and/or differentiation. Some recent work elegantly illustrates the role of sphingolipids during oligodendroglial differentiation (Bansal et al, 1999;Hirahara et al, 2004;Yaghootfam et al, 2005). For example, absence of sulfatides stimulates a premature differentiation of OLPs.…”

“…Second, transplants were done at a postnatal time when MLD pups had a delayed myelination (Yaghootfam et al, 2005). This condition likely facilitated transplanted OLPs, carrying the selective advantage of a normal sphingolipid catabolism, to migrate and myelinate the MLD brain.…”

Increasing Sulfatide Synthesis in Myelin-Forming Cells of Arylsulfatase A-Deficient Mice Causes Demyelination and Neurological Symptoms Reminiscent of Human Metachromatic Leukodystrophy

“…Myelin was purified from total brains by sucrose gradient centrifugation, as described previously (Norton and Poduslo, 1973). Purified myelin, total brain samples, or peripheral nerves (plexus brachialis, sciatic nerve) were homogenized in 20 vol of chloroform/methanol (2:1), and sphingolipids were isolated as described previously (Yaghootfam et al, 2005). Lipid samples were loaded onto silica gel 60 thinlayer chromatography (TLC) plates (Merck) manually or using an automatic TLC sampler (CAMAG, Berlin, Germany) and developed using chloroform/methanol/water (60:27:4, v/v/v) as the solvent system.…”

Dysfunction of Platelet-derived Growth Factor Receptor α (PDGFRα) Represses the Production of Oligodendrocytes from Arylsulfatase A-deficient Multipotential Neural Precursor Cells

“…Active Myelination in ASA Ϫ/Ϫ Animals-Previous studies performed in ASA Ϫ/Ϫ animals during the peak of myelination showed a delayed expression of mRNA for myelin proteins: MBP, myelin and lymphocyte protein, and PLP, which suggests a defect in the differentiation program of OLs in the ASA Ϫ/Ϫ context (38). We have examined the expression of PDGFR␣ and MBP by immunohistochemistry in the cortex of ASA ϩ/ϩ and ASA Ϫ/Ϫ mice during the period of active myelination at postnatal days 7, 14, and 21 ( Fig.…”