LIMES c/o Kekulé-Institut, University of Bonn, Bonn, Germany
Proc Jpn Acad Ser B Phys Biol Sci. 2012;88(10):554-82. doi: 10.2183/pjab.88.554.
Analysis of lipid storage in postmortem brains of patients with amaurotic idiocy led to the recognition of five lysosomal ganglioside storage diseases and identification of their inherited metabolic blocks. Purification of lysosomal acid sphingomyelinase and ceramidase and analysis of their gene structures were the prerequisites for the clarification of Niemann-Pick and Farber disease. For lipid catabolism, intraendosomal vesicles are formed during the endocytotic pathway. They are subjected to lipid sorting processes and were identified as luminal platforms for cellular lipid and membrane degradation. Lipid binding glycoproteins solubilize lipids from these cholesterol poor membranes and present them to water-soluble hydrolases for digestion. Biosynthesis and intracellular trafficking of lysosomal hydrolases (hexosaminidases, acid sphingomyelinase and ceramidase) and lipid binding and transfer proteins (GM2 activator, saposins) were analyzed to identify the molecular and metabolic basis of several sphingolipidoses. Studies on the biosynthesis of glycosphingolipids yielded the scheme of Combinatorial Ganglioside Biosynthesis involving promiscuous glycosyltransferases. Their defects in mutagenized mice impair brain development and function.
对无脑痴呆症患者死后大脑中的脂质储存进行分析，导致发现了五种溶酶体神经节苷脂贮积症，并确定了它们的遗传性代谢障碍。溶酶体酸性鞘磷脂酶和神经酰胺酶的纯化以及它们基因结构的分析，是阐明尼曼-皮克病和法伯病的前提条件。对于脂质代谢，内体小泡在胞吞途径中形成。它们经历脂质分选过程，并被鉴定为细胞脂质和膜降解的腔室平台。脂质结合糖蛋白将这些胆固醇含量低的膜中的脂质溶解，并将其呈递给水溶性水解酶进行消化。溶酶体水解酶（己糖胺酶、酸性鞘磷脂酶和神经酰胺酶）以及脂质结合和转运蛋白（GM2 激活剂、神经鞘脂激活蛋白）的生物合成和细胞内运输进行了分析，以确定几种鞘脂贮积症的分子和代谢基础。糖脂生物合成的研究得出了涉及混杂糖基转移酶的组合神经节苷脂生物合成方案。它们在突变小鼠中的缺陷会损害大脑发育和功能。
