Metabolic abnormalities in feline Niemann-Pick type C heterozygotes
Metabolic abnormalities in feline Niemann-Pick type C heterozygotes
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DOI：
10.1007/bf01799262
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发表时间：
1996-01-01
影响因子：
4.2
通讯作者：
Just, CA
中科院分区：
文献类型：
--
作者：
Brown, DE;Thrall, MA;Just, CA
C 型尼曼-匹克病 (NPC) 是一种常染色体隐性遗传性神经内脏溶酶体贮积症，其中胆固醇脂质沉积症是由未酯化胆固醇的细胞内运输缺陷引起的。 NPC 的主要分子缺陷尚不清楚；胆固醇代谢的调节机制受损，导致外源胆固醇的酯化延迟，未酯化的胆固醇在溶酶体中积累，并二次储存糖脂和鞘磷脂。在来自猫科动物 NPC 模型的专性杂合子中，用外源衍生的胆固醇攻击的培养的皮肤成纤维细胞表现出中等的胆固醇酯化率和未酯化胆固醇的积累。专性杂合子猫的肝脏脂质分析显示胆固醇和鞘磷脂浓度处于中等水平。在 3 只杂合子猫中，有 2 只发现了空泡皮肤成纤维细胞，偶尔皮质神经元表现出对 GM2-神经节苷脂具有免疫反应性的细胞内包涵体。超微结构研究提供了肝脏和大脑中储存的证据。我们相信这些形态学和生化发现是神经元贮积病遗传携带者中枢神经系统异常表现的第一个例子。
Niemann-Pick disease type C (NPC) is an autosomal recessive neurovisceral lysosomal storage disorder in which cholesterol lipidosis results from defective intracellular transport of unesterified cholesterol. The primary molecular defect of NPC is unknown; regulatory mechanisms of cholesterol metabolism are impaired, resulting in retarded esterification of exogenous cholesterol with accumulation of unesterified cholesterol in lysosomes and secondary storage of glycolipids and sphingomyelin. In obligate heterozygotes from a feline NPC model, cultured skin fibroblasts challenged with exogenously derived cholesterol exhibited intermediate rates of cholesterol esterification and accumulation of unesterified cholesterol. Liver lipid analyses of obligate heterozygote cats demonstrated intermediate cholesterol and sphingomyelin concentrations. Vacuolated skin fibroblasts were found in 2 of 3 heterozygote cats, and occasional cortical neurons exhibited intracellular inclusions immunoreactive for GM2-ganglioside. Ultrastructural studies provided evidence of storage in liver and brain. We believe these morphological and biochemical findings are the first example of manifestations of CNS abnormalities in a genetic carrier for a neuronal storage disease.