Karten Barbara, Vance Dennis E, Campenot Robert B, Vance Jean E
Canadian Institutes of Health Research Group on the Molecular and Cell Biology of Lipids and Departments of Medicine, Biochemistry and Cell Biology, University of Alberta, Edmonton, Alberta, Canada.
J Neurochem. 2002 Dec;83(5):1154-63. doi: 10.1046/j.1471-4159.2002.01220.x.
Niemann-Pick type-C (NPC) disease is characterized by a progressive loss of neurons and an accumulation of unesterified cholesterol within the endocytic pathway. Unlike other tissues, however, NPC1-deficient brains do not accumulate cholesterol but whether or not NPC1-deficient neurons accumulate cholesterol is not clear. Therefore, as most studies on cholesterol homeostasis in NPC1-deficient cells have been performed in fibroblasts we have investigated cholesterol homeostasis in cultured murine sympathetic neurons lacking functional NPC1. These neurons did not display obvious abnormalities in growth or morphology and appeared to respond normally to nerve growth factor. Filipin staining revealed numerous cholesterol-filled endosomes/lysosomes in NPC1-deficient neurons and the mass of cholesterol in cell bodies was greater than in wild-type neurons. Surprisingly, however, the cholesterol content of NPC1-deficient and wild-type neurons as a whole was the same. This apparent paradox was resolved when the cholesterol content of NPC1-deficient distal axons was found to be less than of wild-type axons. Cholesterol sequestration in cell bodies did not depend on exogenously supplied cholesterol since the cholesterol accumulated before birth and did not disperse when neurons were cultured without exogenous cholesterol. The altered cholesterol distribution between cell bodies and axons suggests that transport of cholesterol, particularly that synthesized endogenously, from cell bodies to distal axons is impaired in NPC1-deficient neurons.
尼曼-匹克C型（NPC）病的特征是神经元进行性丧失以及内吞途径中未酯化胆固醇的积累。然而，与其他组织不同，NPC1缺陷的大脑不会积累胆固醇，但NPC1缺陷的神经元是否积累胆固醇尚不清楚。因此，由于大多数关于NPC1缺陷细胞中胆固醇稳态的研究是在成纤维细胞中进行的，我们研究了缺乏功能性NPC1的培养小鼠交感神经元中的胆固醇稳态。这些神经元在生长或形态上没有表现出明显异常，并且似乎对神经生长因子有正常反应。荧光素染色显示NPC1缺陷的神经元中有大量充满胆固醇的内体/溶酶体，细胞体中的胆固醇量大于野生型神经元。然而，令人惊讶的是，NPC1缺陷和野生型神经元的总体胆固醇含量是相同的。当发现NPC1缺陷的远端轴突的胆固醇含量低于野生型轴突时，这个明显的矛盾得到了解决。细胞体中的胆固醇隔离不依赖于外源性供应的胆固醇，因为胆固醇在出生前就已积累，并且在没有外源性胆固醇的情况下培养神经元时不会分散。细胞体和轴突之间胆固醇分布的改变表明，在NPC1缺陷的神经元中，胆固醇从细胞体向远端轴突的运输，特别是内源性合成的胆固醇的运输受到了损害。
