Study on the mechanism of demyelination in hereditary leukodystrophy

在几种遗传性白质营养不良症中，蟹病（GLD）是独特的，因为缺乏缺乏酶的天然底物，半乳糖神经酰胺的积累。我们最近证明了半乳糖神经酰胺的水解是由两种遗传上不同的酸性β -半乳糖苷酶（半乳糖神经酰胺酶I和II）催化的，其中一种(I)缺乏GLD。半乳糖酪氨酸是半乳糖神经酰胺酶I的良好底物，但不是半乳糖神经酰胺酶II的良好底物。Svennerholm等人报道了GLD患者脑内脂质积累，但测定方法过于复杂且耗时。我们利用高效液相色谱技术建立了一种简单、灵敏的半乳糖旋腺苷含量测定方法，并证实了半乳糖旋腺苷脂质不仅在大脑中，而且在人类和小鼠GLD患者的躯体器官中都有异常的积累。半乳糖旋氨醇积累的组织分布和细胞毒性强烈提示半乳糖旋氨醇积累与GLD脱髓鞘密切相关。经半乳糖基转移酶的催化，由游离的自旋体碱合成半乳糖糖苷。在偏色差性脑白质营养不良症（MLD）中，我们发现溶硫脂异常积聚。脑白质、脊髓和周围神经的累积量较高。脂质也具有很强的细胞毒性，积累的溶硫脂可能导致MLD患者脱髓鞘，就像GLD患者一样。进一步研究这些溶酶化合物对髓细胞（雪旺细胞和少突胶质细胞）的毒性作用将是必要的。

Among several hereditary leukodystrophies, krabbe disease (GLD) is unique because of the absence of accumulation of a natural substrate of the deficient enzyme, galactosylceramide. We have recently demonstrated that the hydrolysis of galactosylceramide is catalyzed by two genetically distinct acid beta-galactosidases (galactosylceramidase I and II) and one of them (I) is deficient in GLD. Galactosylspingosine (psychosine) is a good substrate of galactosylceramidase I but not galactosylceramidase II. Svennerholm et al reported an accumulation of the lipid in the brain of GLD patients but the assay method was too complex and time-consuming. We developed a simple and sensitive assay method of galactosylspingosine using high-performance liquid chromatography, and demonstrated an abnormal accumulation of the lipid not only in the brain but also in somatic organs of human and murine cases of GLD. The tissue distribution of the accumulation and the cytotoxicity of galactosylspingosine strongly suggested the close relationship between the accumulation of galactosylsphingosine and demyelination seen in cases of GLD. Galactosylsphingosine was found to be synthesized from free spingoid bases by the catalysis of galactosyltransferase.In metachromatic leukodystrophy (MLD), we found an abnormal accumulation of lysosulfatide. The accumulated amount was high in the cerebral white matter, spinal cord and peripheral nerve. The lipid was also so cytotoxic that accumulated lysosulfatide may cause demyelination in patients with MLD as in the case of GLD.Further studies concerning toxic effects of these lyso-compounds to myelinforming cells (Schwann cells and oligodendrocytes) will be necessary.