METABOLISM OF COMPLEX LIPIDS OF NERVOUS TISSUES

1. D型尼曼-皮克患者的代谢缺陷

1. The metabolic defect in patients with Type D Niemann-Pick disease (Nova Scotia variant) has been shown to be due to abnormal intracellular cholesterol homeostasis that resembles, but differs in some respects, from the abnormality in Type C Niemann-Pick disease previously discovered by this Branch. The molecular lesion in these disorders results in: (1) failure to down- regulate LDL receptors on cell membranes; (2) lack of down- regulation of HMGCoA reductase, a key enzyme in cholesterol biosynthesis; and (3) inability to up-regulate acyl cholesterol acyl CoA transferase, the enzyme that catalyzes the esterification of intracellular cholesterol. Based on this information, we have developed tests for the diagnosis of Types C and D Niemann-Pick disease and the identification of heterozygotes. In FY 87 these procedures were shown to be reliable for the prenatal diagnosis of these conditions. 2. Other work has centered on the synthesis and use of non- metabolizable analogs of glucocerebroside and galactocerebroside to examine the pathogenesis of Gaucher's disease and Krabbe's disease by developing rodent models of the respective human disorders. A novel analog of glucocerebroside has been synthesized and appears to be useful for the selection of mutagenized cells that lack glucocerebrosidase, the enzyme lacking in Gaucher's disease. These cells will be used to construct a transgenic murine analog of Gaucher's disease.