Study on the mechanism of demyelination in hereditary leukodystrophy

遗传性脑白质营养不良脱髓鞘机制研究

基本信息

批准号：
63570367
负责人：
KOBAYASHI Takuro
金额：
$ 1.47万
依托单位：
KYUSHU UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1988
资助国家：
日本
起止时间：
1988 至 1989
项目状态：
已结题

项目摘要

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.

在几种遗传性白细胞营养不良菌中，克拉布疾病（GLD）是独一无二的，因为缺乏缺乏酶的天然底物，甲乳乳糖酰胺的自然基质。我们最近证明了半乳糖基酰胺的水解是由两种遗传上不同的酸β-半乳糖苷酶（半乳糖基酰胺酶I和II）催化的，其中一个（i）在GLD中不足。半乳糖基苯甲酰氨基（Psychosine）是半乳糖苷酶I的良好底物，但不是半乳糖基酶酶II。 Svennerholm等人报道了GLD患者大脑中脂质的积累，但测定方法太复杂且耗时。我们使用高性能的液相色谱法开发了一种简单敏感的分析方法，用于半乳糖基苯甲酰氨酸，并证明了脂质的异常积累不仅在大脑中，而且在人类和鼠类GLD的体细胞器官中也存在。聚集体的积累的组织分布和半乳糖苷的细胞毒性强烈表明，在GLD病例中看到半乳糖基肾上腺素的积累与脱髓鞘之间的紧密关系。发现半乳糖基肾上腺素是通过半乳糖基转移酶的催化从游离的黄瓜碱中合成的。在实质性白细胞营养不良症（MLD）中，我们发现溶酶硫化物的异常积累。脑白质，脊髓和周围神经的累积量很高。脂质也是如此的细胞毒性，以至于在GLD的情况下，MLD患者的积累可能会导致脱髓鞘。有关这些溶血化合物对髓质成型细胞（Schwann细胞和少突胶质细胞）的毒性作用的研究是必要的。